Document 6430933

Transcription

Document 6430933

Physicochemical Studies on Different Vital
V
kinds
of Metal-drug
drug Binding and their Application
pplication
A peer reviewed book …..
By
Moamen S. Refat,
Refat Samy M. El-Megharbel
egharbel and
Abdel Majid A. Adam
International E – Publication
www.isca.me , www.isca.co.in
Physicochemical Studies on
Different Vital Kinds of MetalDrug Binding and their
Application
(A peer reviewed book)
Moamen S. Refat
Professor of Inorganic Chemistry
Samy M. El-Megharbel
Ass. Professor of Inorganic Chemistry
Abdel Majid A. Adam
Ass. Professor of Inorganic Chemistry
Chemistry Department, Faculty of
Science, Taif University
2013
International E - Publication
International E - Publication
427, Palhar Nagar, RAPTC, VIP-Road, Indore-452005 (MP) INDIA
Phone: +91-731-2616100, Mobile: +91-80570-83382
E-mail: [email protected] , Website: www.isca.me , www.isca.co.in
© Copyright Reserved
2013
All rights reserved. No part of this publication may be reproduced, stored,
in a retrieval system or transmitted, in any form or by any means,
electronic, mechanical, photocopying, reordering or otherwise, without the
prior permission of the publisher.
ISBN: 978-93-83520-26-8
TABLE OF CONTENTS
Topic
Page
Preface.
Chapter 1:
1-1- Perspectives of metal ions in medicine.
1-2- Metal carboxylate review.
1-2-1- Monocarboxylates.
Chapter 2:
2-1- Antibiotic Drugs.
Chapter 3:
3-1- Analgesics Drugs.
Chapter 4:
4-1- Anti-rheumatic Drugs.
Chapter 5:
5-1- Antihistaminic drugs (Histamine antagonist).
Chapter 6:
6-1- Folic acid.
Chapter 7:
7-1- Bleomycin and Streptonigrin metal complexes.
Chapter 8:
8-1- Different antibiotic metal complexes.
Chapter 9:
9-1-Metal complexes of purines and their derivatives.
Chapter 10:
10-1- Metformin hydrochloride complexes.
Chapter 11:
11-1- Pyridoxine hydrochloride (Vitamin B6).
Chapter 12:
12-1- Enalapril Maleate.
About the Authors
International Science Congress Association
iii
iv
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2
3
12
51
65
81
84
87
90
101
104
111
117
120
PREFACE
During the past two decades, considerable attention has been paid to the
chemistry of the metal complexes. It has been suggested that the presence of metal ions
in biological fluids could have a significant effect on therapeutic action of drugs. The
successful synthesis and application of novel metal complexes can have a great impact
on all areas of chemistry and biology. So, we have synthesis some complexes
containing nucleous molecule which have a widely known concerning the biological
application in our life to study them.
As yet from the literature survey, little information is available about the
compounds, which are effective as coordinating ligands with the functional sites amino,
hydroxyl, carbonyl and carboxyl groups. In view of the biological, physico-chemical
properties and industrial importance of these ligands and their metal complexes, the aim
of the present work is to shed light on:
•
•
•
Understanding the nature of interaction and chelation between metal ions and
these ligands
Investigating the physico-chemical properties of the ligands and their metal
complexes
Screening of the ligands and their metal complexes for their biological activity.
iv
CHAPTER 1
1-1- Perspectives of metal ions in medicine
Metals and metal complexes have played key role in the development of modern
chemotherapy [1]. For example, anticancer platinum drugs appear in more chemotherapy
regimens than any other class of anticancer agents and have contributed substantially to the
success achieved in treating cancer over the past three decades. Metals can play an important
role in modifying the pharmacological properties of known drugs after coordinating to a metal.
This is because of the resulting prodrugs have different physical and pharmacological
properties, allowing the drug to be released in a controlled fashion or at specific location [2].
This approach may lead to the rescue of drugs that have failed because of poor pharmacology or
high toxicity. For example, complexation of nonsteroidal anti-inflammatory drugs to copper
overcomes some of the gastric side effects of these drugs [3]. The release of cytotoxins such as
nitrogen mustards from redox-active metals such as cobalt in the hypoxic regions of solid
tumors has the potential to improve drug activity and reduce toxicity [4]. The metal based drugs
are also being used for the treatment of a variety of ailments viz. diabetes, rheumatoid arthritis,
inflammatory and cardiovascular diseases as well as diagnostic agents [5-7].
In medicinal chemistry, metal complexes have received limited attention as compared
to organic compounds. In fact, many organic compounds used in medicine do not have a purely
organic mode of action and require traces of metal ions directly or indirectly for activation or
biotransformation. Our health, aging, physiological disorders and diseases are related to the state
of the metal ions and their complexes with biomolecules in the body. The amount of metals
present in the human body is approximately 0.03% of the body weight. Low metal ion
concentrations may be harmful for the body. It has been reported that [8] in cancerous parts of
the kidney, the concentrations of Cd, Cr, Ti, V, Cu, Se, and Zn were found to be at a lower level
than in the noncancerous parts. Ligands having electron donor atoms like N, O, S, and P etc.
may form coordination bond with metal ion. Chelation causes drastic changes in biological
properties of ligands as well as metal moiety and in many cases it causes synergistic effect of
both metal ion and ligand [9, 10].
A number of drugs and potential pharmaceutical agents also contain metal-binding or
metal-recognition sites, which can bind or interact with metal ions and potentially influence
their bioactivities and might also cause damages on their target biomolecules. Numerous
examples of these ‘‘metallodrugs’’ and ‘‘metallopharmaceuticals’’ and their actions can be
found in the literature, for instance: (a) several anti-inflammatory drugs, such as aspirin and its
metabolite salicylglycine [11-14], suprofen [15], and paracetamol [16] are known to bind metal
ions and affect their antioxidant and anti-inflammatory activities; (b) the potent histamine-H2receptor antagonist cimetidine [17] can form complexes with Cu2+ and Fe3+, and the histidine
blocker antiulcer drug famotidine can also form stable complex with Cu2+ [18, 19]; (c) the
anthelmintic and fungistatic agent thiabendazole, which is used for the treatment of several
parasitic diseases, forms a Co2+ complex of 1:2 metal to drug ratio [20] (d) the Ru2+ complex of
the anti-malaria agent chloroquine exhibits an activity two to five times higher than the parent
drug against drug-resistant strains of Plasmodium faciparum [21]. However, it is known that
some drugs act via chelation or by inhibiting metalloenzymes but most of the drugs act as
potential ligands, a lot of studies are being carried out to ascertain how metal binding influences
1
the activities of the drugs [22]. Metal complexes are gaining increasing importance in the design
of drugs on coordination with a metal.
Also, lanthanides ions coordinate to some vital drugs for instance; syntheses,
characterization, antioxidative and antitumor activities of solid quercetin rare earth (III)
complexes were studied [23]. The results show that the suppression ratio of the complexes
against the tested tumor cells are superior to quercetin·2H2O. Pharmacological activity studies
of Lanthanide complexes with Mendiaxon and Hymecromone showed marginal cytotoxic
activity against transformed leukemic cell lines (P3HR1 and THP-1) as compared to the
inorganic salts [24]. Some rare earth chelates of naphthoquinone antibacterials were studied
[25]. Synthesis, characterization, and antiinflammatory activity of Naproxen complexes with
rare earth (III) show enhancement of antiinflammatory activity relative to the ligand [26]. The
results show that the complexes of rare earth metals (III), (i.e. La, Ce, Pr, Nd, Sm Eu, Gd and
Tb) with 2-(4,6-dimethyl)-2-pyrimidinyl)thio)-acetic acid (LnL3-nH2O; n = 4 or 5), against the
tested tumour cells (HL-60 human leukemia cell lines, BGC-823 human gastric carcinoma cell
lines, hela human cervix adenocarcinoma cell lines and Bel-7402 human hepatic carcinoma cell
lines) are superior to the ligand [27]. Experimental results indicated that phthalazin-1(2H)-one
and the complex can bind to DNA by intercalation modes, but the binding affinity of La(III)complex is higher than that of the ligand. The La(III)-complex of phthalazin-1(2H)-one,
[La(NO3)3·4H2O·C8H7N2O]·H2O, was synthesized and characterized on the basis of elemental
analysis, thermal analyses (TG/DTA) and X-ray crystallography, the comparative antitumor
activities of La(III)-complex was also investigated [28]. Herbicides (chlorophenoxyalkanoic
acids) interact with Ca(II), Gd(III) and Ce(III) to form complexes, which were tested against a
few common bacteria by minimum inhibitory concentration (MIC) experiments exhibiting not
any antimicrobial action at concentrations up to 1600 μg/ml [29].
A series of vitamin B6 pyridoxol complexes with, e.g. La, Ce, Pr, Nd, Sm, Eu, Gd, Ho,
Er, and Y, M(PN)5Cl3.6H2O (where: PN = pyridoxol), were synthesized and characterized by
elemental analysis, molar conductance, TGA-DTA, IR, and 1HNMR spectroscopic techniques.
The antioxidative activity of complexes was determined, using the suppression ratio of activated
oxygen as an indicator. The results show that the complexes have the scavenger effects for
activated oxygen [30]. The encouraging results of preclinical and clinical studies with metal
complexes form the basis for further investigations towards the development of metallodrugs
for better healthcare.
1-2- Metal carboxylate review
The metal carboxylates have emerged as an important family in the last few years. This
family includes not only mono- and dicarboxylates of transition, rare-earth, and main-group
metals, but also a variety of hybrid structures. Some of the carboxylates possess novel
adsorption and magnetic properties. Dicarboxylates and related species provide an effective
means of designing novel hybrid structures with porous and other properties. In some of these
structures, the dicarboxylate acts as a linker between two inorganic units. In recent years the area
of inorganic open-framework materials has become one of intense research activity [31-36]
While one of the objectives of the research into openframework solids is to find materials
possessing channels and other features that make them porous, which can impart potential
2
catalytic and sorption properties, the discovery of fascinating architectures of different
dimensionalities has been equally exciting. The aluminosilicates and metal phosphates, which
constitute important prototype open-framework materials, have been discussed widely in the
literature [31].
Several openframework phosphates with dimensionalities varying between zero and three have
been synthesized and characterized [32]. A limitation with metal phosphates is that the
structures comprise rigid polyhedra, such as tetrahedra and octahedra, which constitute the
primary building units [32-35]. There has been much interest in designing hybrid materials
containing inorganic and organic linkers, and several metal–organic frameworks possessing
zeolitic structures have been reported [32, 37–39] One of the preoccupations today is to design
novel structures involving both organic and inorganic components by employing novel
synthetic tools as well as supramolecular chemistry. The design of hybrid structures takes
advantage of metal coordination as well as the functionalities of the organic components, since
the flexibility of the organic linkers renders such open architectures attractive [35, 36–43]. The
metal carboxylates are particularly interesting in that they not only form open-framework
structures resulting from the presence of the carboxylate function itself, but also where the
carboxylate group acts as a linker between inorganic moieties. Another interesting variety exists
where the carboxylate unit coexists with a phosphate or arsenate group to give a hybrid
structure. Some of the novel architectures of carboxylates are obtained by varying the nature of
the reactants or the synthetic conditions, and by carrying out reactions in the presence of
additives such as organic amines; the reactions are performed under hydro/solvothermal
conditions. Accordingly, simple metal carboxylates such as formates and acetates crystallize in
unusual structures under hydrothermal conditions [36, 44].
In this Review, we present a concise review of the structures and properties of the several of
families of metal carboxylates. The Review is divided into six sections dealing with
monocarboxylates, oxalates, aliphatic dicarboxylates, multifunctional dicarboxylates, hybrid
compounds, and cadmium oxalates incorporating alkali halides. Strategies to design carboxylate
networks are highlighted, and the comprehensive list of references provides linhs to the most
up-todate information. We particularly wish to recognize the review by Cheetham et al., [32]
primarily dealing with openframework metal phosphates, which appeared in this journal in
1999.
1-2-1- Monocarboxylates
Systematic investigations of open-framework structures constructed from
monocarboxylate units are rather limited, but some of the metal monocarboxylates coexist with
other ligands to form extended lattices of varying dimensionalities [44]. For example, copper
formate tetrahydrate exhibits two-dimensional (2D) copper formate layers [45] that are
separated by water molecules, while bismuth formate has a one-dimensional (1D) chain
structure [46]. Monocarboxylates of alkali metals exhibit several polymorphic modifications
[47]. Metal acetates tend to form dimers [44, 48] the classic example being copper diacetate,
which with further association forms an infinite array [49]. An interesting layeredcompound
based on copper acetate is [{Cu2(O2CMe)4}-(tpt)2]·2MeOH, (tpt=2,4,6-tris(4-pyridyl-1,3,5-
3
triazine), which exhibits a large-pore structure; the metal acetate dimers are linked by N-donor
ligands (Fig. 1-1) [50].
Fig. 1-1: [{Cu2(O2CMe)4}- (tpt)2]·2MeOH.
The organic groups link the acetate dimers, thus avoiding interpenetration
through interlayer p–p interactions, which serves to stabilize the structure. Cotton and
Kim [51] have employed cyanide ligands to connect metal acetate dimers to form
molecular boxes and layered structures, thus providing a new avenue for the
construction of neutral frameworks. For example, [Rh2(O2CCF3)42(TCNE)]·2C6H6
(TCNE=tetracyanoethylene) (Fig. 1-2) contains non-interpenetrating sheets formed by
quasi-rectangular 30-membered rings. The sheets are again stabilized by significant p–p
interactions between the {Rh2(O2CCF3)4} and TCNE moieties [51]. The TCNE units
themselves are linked via {Rh2(O2CCF3)4} moieties, thus demonstrating the bridging
role of the rhodium carboxylate complexes. Jacobson et al. [52] have prepared
K3[Co(CN)6]·2[Rh(O2CMe)4], in which the {Rh2(O2CMe)4} dimers are linked through
the octahedral {Co(CN)6} unit to form a 2D structure with large windows. High
nuclearity inorganic clusters which formed by acetate ligands yield novel structures with
interesting properties. Such clusters represent a bridge between molecular chemistry and
solid-state chemistry, and provide a means of understanding their size-dependent
physical properties [53]. Hydroxo, oxo, and carboxylate groups are used to prepare new
nanoscopic compounds with such clusters, in which hydrophilic groups lie within the
4
core and hydrophobic groups are located at the periphery [54]. High-nuclearity clusters
can also be assembled into infinite coordination polym Dong et al., [55].
Fig. 1-2: Neutral framework for [Rh2(O2CCF3)42(TCNE)]·2C6H6
Microporous metal hydroxyacetates exhibiting ionexchange behavior have also
been reported [56]. The 3D cobalt hydroxyacetate [Co5(OH)2(O2CMe)8]·2H2O has a
structure that is built up entirely through edge-sharing cobalt–oxygen octahedral [57].
The acetate ligands, generated in situby oxidative hydrolytic cleavage of an
acetylacetonate ligand, exhibit both h1:h2 and the unusual h2:h2 coordination modes.
Recently, the 2D copper acetate [Cu(Me- CO2)(MeO)] was reported, in which acetate
ligands containing tricoordinated oxygen atoms are found in addition to bridging
methoxo groups [58]. In (pipzH2)(H3O)[Al15(m3-O)4(m3-OH)6(m-OH)14(hpdta)4]
·pipz·41H2O pipz=piperazine, H5hpdta=2-hydroxypropane-1,3-diamine-N,N,N’,N’tetra acetic acid), [59]. All aggregates with aluminium oxyhydroxide cores (of the
brucite type) are assembled through hpdta linker groups. Several structural motifs based
on or related to carboxylates are profitably employed in the design of new solids with
open structures [60]. Among the many structural motifs commonly used in
supramolecular chemistry [60], the simplest is the hydrogen-bonded dimer (a). The
replacement of the proton in the dimer by various metal–acetate moieties (b–d)
facilitates the assembly of 3D supramolecular networks through out-of-plane linkages.
The use of the acetate dimer as a secondary building unit (SBU) in the design of rigid
3D metal–organic frameworks will be examined later in this Review. Paddle-wheel
metal acetate clusters have been used to assemble encoded organic nodes (Fig. 1-3)
[61]. This gives rise to an “inverted” metal–organic framework with compartmentalized
cavities and walls that are accessible for further functionalization of the channels.
5
Fig. 1-3: Paddle-wheel metal acetate clusters.
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REFERENCES
1- Baslas, R.K., Zamani, R. and Nomani, A.A., Experientia, 35, 455 (1979).
2- Gonzalez, B.E., Daeid, N.N., Nolan, K.B. and Farkas, E., Polyhedron, 13, 1495
(1994).
3- Nolan, K.B. and Soudi, AA., Inorg. Chim. Acta, 230, 209 (1995).
4- Muller, J.G. and Burrows, C.J., Inorg. Chim. Acta, 275, 314 (1998).
5- Underhill, A.E., Bougourd, S.A., Flugge, M.L., Gale, S.E. and Gomm, P.S., J. Inorg.
Biochem., 52, 139 (1993).
6- Kirkova, M., Atanassova, M. and Russanov, E., Gen. Pharmacol., 33, 271 (1999).
7- Duda, A.M., Kowalik-Jankowska, T., Kozlowski, H. and Kupka, T., J. Chem. Soc.
Dalton Trans., 2909 (1995).
8- Kubiak, M., Duda, A.M., Ganadu, M.L., Kozlowski, H., J. Chem. Soc. Dalton
Trans., 1905 (1996).
9- Umadevi, B., Muthiah, P.T., Shui, X. and Eggleston, D.S., Inorg. Chim. Acta,
234,149 (1995).
10- Sanchez-del Grado, R.A., Navarro, M., Perez, H. and Urbina, J.A., J. Med. Chem.,
39, 1095 (1996).
11- Ball P (2000). "Quinolone generations: natural history or natural selection?". J.
Antimicrob. Chemother. 46 Suppl T1 (Supplement 3): 17–24. PMID 10997595.
http://jac.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=10997595.
12- "New Classification and Update on the Quinolone Antibiotics - May 1, 2000 American Academy of Family Physicians". http://www.aafp.org/afp/20000501/
2741.html. Retrieved 2008-03-18.
13- Nalidixic Acid, case number 389-08-02, listing mechanism AB, NTP (1989)b.
14- Oliphant CM, Green GM (February 2002). "Quinolones: a comprehensive review".
Am Fam Physician 65 (3): 455–64. PMID 11858629. http://www.aafp.org/afp/
20020201/455.html.
6
15- Paul G. Ambrose; Robert C. Owens, Jr (1 March 2000). "Clinical Usefulness Of
Quinolones". Seminars in Respiratory and Critical Care Medicine (Medscape).
http://www.medscape.com/viewarticle/410872_6.
16- The European Medicines Agency (24 July 2008). "EMEA Restricts Use of Oral
Norfloxacin Drugs in UTIs". Doctor's Guide. http://www.docguide.com/news/
content.nsf/news/852571020057CCF68525749000687709.
17- Schmid, Randolph E. (May 1, 2006). "Drug Company Taking Tequin Off Market".
Associated Press. http://www.sfgate.com/cgi-bin/article.cgi?file=/news/archive/
2006/05/01/national/w120748D88.DTL&type=health. Retrieved 2006-05-01.
18- Fiscella RG, Lewis CC, Jensen MK (October 2007). "Topical ophthalmic fourthgeneration fluoroquinolones: Appropriate use and cost considerations". Am J Health
Syst Pharm 64 (19): 2069–73. doi:10.2146/ajhp060667. PMID 17893419.
http://www.ajhp.org/cgi/pmidlookup?view=long&pmid=17893419.
19- The European Medicines Agency (EMEA); Danish Medicines Agency (24 July
2008). "EMEA recommends restricting the use of oral moxifloxacin-containing
medicines".
20- Miravitlles M, Anzueto A (July 2008). "Moxifloxacin: a respiratory
fluoroquinolone". Expert Opin Pharmacother 9 (10): 1755–72. doi:10.1517/
14656566.9.10.1755. PMID 18570608.
21- UN (2005). "Consolidated list of products - Pharmaceuticals 12th issue" (PDF).
United Nations. http://www.un.org/esa/coordination/CL12.pdf.
22- Paul G. Ambrose; Robert C. Owens, Jr (1 March 2000). "New Antibiotics in
Pulmonary and Critical Care Medicine: Classification Of Quinolones By
Generation". USA: Medscape. http://www.medscape.com/viewarticle/410872_4.
23- sanofi-aventis U.S. LLC (September 2008). "NegGram® Caplets (nalidixic acid,
USP)" (PDF). USA: FDA. http://www.accessdata.fda.gov/drugsatfda_docs/label
/2009/014214s058lbl.pdf.
24- Wentland MP: In memoriam: George Y. Lesher, Ph.D., in Hooper DC, Wolfson JS
(eds): Quinolone antimicrobial agents, ed 2., Washington DC, American Society for
Microbiology : XIII - XIV, 1993.
25- Hooper, DC. (Mar-Apr 2001). "Emerging mechanisms of fluoroquinolone
resistance." (PDF). Emerg Infect Dis 7 (2): 337–41. doi:10.3201/eid0702.010239.
PMID 11294736. PMC 2631735. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC
2631735/pdf/11294736.pdf.
26- Elsea, SH.; Osheroff, N.; Nitiss, JL. (July 1992). "Cytotoxicity of quinolones toward
eukaryotic cells. Identification of topoisomerase II as the primary cellular target for
the quinolone CP-115,953 in yeast." (pdf). J Biol Chem 267 (19): 13150–3.
PMID 1320012. http://www.jbc.org/content/267/19/13150.full.pdf.
27- Muto, CA.; Jernigan, JA.; Ostrowsky, BE.; Richet, HM.; Jarvis, WR.; Boyce, JM.;
Farr, BM. (May 2003). "SHEA guideline for preventing nosocomial transmission of
multidrug-resistant strains of Staphylococcus aureus and enterococcus.". Infect
Control Hosp Epidemiol 24 (5): 362–86. doi:10.1086/502213. PMID 12785411.
7
28- Dr Ralf-Peter Vonberg. "Clostridium difficile: a challenge for hospitals". European
Center for Disease Prevention and Control. Institute for Medical Microbiology and
Hospital Epidemiology: IHE. http://www.ihe-online.com/feature-articles/clostridium
-difficile-a-challenge-for-hospitals/trackback/1/index.html. Retrieved 27 July 2009.
29- Tacconelli, E.; De Angelis, G.; Cataldo, MA.; Pozzi, E.; Cauda, R. (January 2008).
"Does antibiotic exposure increase the risk of methicillin-resistant Staphylococcus
aureus (MRSA) isolation? A systematic review and meta-analysis.". J Antimicrob
Chemother 61 (1): 26–38. doi:10.1093/jac/dkm416. PMID 17986491. http://jac.
oxfordjournals.org/cgi/content/full/61/1/26.
30- Liu, H.; Mulholland, SG. (July 2005). "Appropriate antibiotic treatment of
genitourinary infections in hospitalized patients.". Am J Med 118 Suppl 7A: 14S–
20S. doi:10.1016/j.amjmed.2005.05.009. PMID 15993673.
31- a) R. M. Barrer, Hydrothermal Chemistry of Zeolites, Academic Press, London,
1982; b) M. L. Occelli, H. C. Robson, Zeolite Synthesis, American Chemical
Society, Washington, DC, 1989; c) Verified Syntheses of eolitic Materials (Eds.: H.
Robson, K. P. Lillerud, 2nd ed., Elsevier, Amsterdam, 2001; d) M. T. Weller, S. E.
Dann, Curr. Opin. Solid State Mater. Sci. 1998, 3, 137.
32- a) A. K. Cheetham, G. FQrey, T. Loiseau, Angew. Chem. 1999, 111, 3466; Angew.
Chem. Int. Ed. 1999, 38, 3268; b) J. M. Thomas, Angew. Chem. 1999, 111, 3800;
Angew. Chem. Int. Ed. 1999, 38, 3588; c) J. M. Thomas, Chem. Eur. J. 1997, 3,
1557; d) G. FQrey, C. R. Acad. Sci. Ser. IIc 1998, 1; e) F. SchRth, W. Schmidt,
Adv. Mater. 2002, 14, 629; f) Supramolecular Organization and Materials Design
(Eds.: W. Jones, C. N. R. Rao), Cambridge University Press, Cambridge, 2002; g)
C. N. R.Rao, Proc. Indiana Acad. Sci. 2002, 113, 363; h) S. Oliver, A. Kuperman,
G. A. Ozin, Angew. Chem. 1998, 110, 48; Angew. Chem. Int. Ed. Engl. 1998, 37,
46.
33- a) A. MRller, H. Reuter, S. Dillinger, Angew. Chem. 1995, 107, 2505; Angew.
Chem. Int. Ed. Engl. 1995, 34, 2311; b) P. Y. Zavilij, M. S. Whittingham, Acta
Crystallogr. Sect. B 1999, 55, 627.
34- a) P. J. Hagrman, D. Hagrman, J. Zubieta, Angew. Chem. 1999, 111, 2798; Angew.
Chem. Int. Ed. 1999, 38, 2638; b) S. R. Batten, R. Robson, Angew. Chem. 1998,
110, 1558; Angew. Chem. Int. Ed. 1998, 37, 1460, and references therein; c) R.
Robson, J. Chem. Soc. Dalton Trans. 2000, 3735; d) S. R. Batten, CrystEngComm
2001, 18, 1.
35- a) G. FQrey, Chem. Mater. 2001, 13, 3084; b) G. FQrey, J. Solid State Chem. 2000,
152, 37, and related articles in the same issue; c) G. FQrey, J. Fluorine Chem. 1995,
72, 187; d) A. Clearfield, Curr. Opin. Solid State Mater. Sci. 1996, 1, 268, and
references therein; e) J. G. Mao, Z. Wang, A. Clearfield, Inorg. Chem. 2002, 41,
2334.
8
36- a) M. Eddaoudi, D. B. Moler, H. Li, B. Chen, T. M. Reineke,M. O'Keeffe, O. M.
Yaghi, Acc. Chem. Res. 2001, 34, 319, and references therein; b) M. Eddaoudi, J.
Kim, D. Vodak, A. Sudik, J. Wachter, M. O'Keeffe, O. M. Yaghi, Proc. Natl. Acad.
Sci. USA 2002, 99, 4900, and related articles in the same issue; c) H. Li, M.
Eddaoudi, M. O'Keeffe, O. M. Yaghi, Nature 1999, 402, 276; d) O. M. Yaghi in
Metal Containing Polymeric Materials, (Eds.: C. U. Pittman, C. E. Carraher, B. M.
Culbertson, M. Zeldin, J. E. Sheets), Plenum, New York, 1996, p. 219; e) O. M.
Yaghi in Modular Chemistry (Ed.: J. Michl), Kluwer, Boston, 1997, p. 663.
37- a) J. M. Lehn, Supramolecular Chemistry, Concepts and Perspectives, VCH,
Weinheim, 1995; b) M. J. Zaworotko, Nature 1999, 402, 242; c) M. J. Zaworotko,
Nature 1997, 386, 220; d) B. Moulton, M. J. Zaworotko, Advances in
Supramolecular Chemistry, Vol. 7, JAI, Greenwich, CT, 2000, p. 235, and
references therein; e) P. J. Langley, J. Hulliger, Chem. Soc. Rev. 1999, 28, 279; f) P.
H. Dinolfo, J. T. Hupp, Chem. Mater. 2001, 13, 3113.
38- a) B. Moulton. M. J. Zaworotko, Chem. Rev. 2001, 101, 1629; b) M. J. Zaworotko,
Angew. Chem. 2000, 112, 3180; Angew. Chem. Int. Ed. 2000, 39, 3052; c) S. I.
Noro, S. Kitagawa, M. Kondo, K. Seki, Angew. Chem. 2000, 112, 2161; Angew.
Chem. Int. Ed. 2000, 39, 2081; d) K. Biradha, Y. Hongo, M. Fujita, Angew. Chem.
2000, 112, 4001; Angew. Chem. Int. Ed. 2000, 39, 3843; e) K. Biradha, Y. Hongo,
M. Fujita, Angew. Chem. 2002, 114, 3545; Angew. Chem. Int. Ed. 2002, 41, 3395;
f) K. Biradha, M. Fujita, Angew. Chem. 2002 , 114, 3542; Angew. Chem. Int. Ed.
2002, 41, 3392; g) M. Fujita, Y. J. Kwon, S. Washizu, O.Ogura, J. Am. Chem. Soc.
1994, 116, 1151.
39- a) C. J. Kepert, M. J. Rosseinsky, Chem. Commun. 1999, 375; b) E. J. Cussen, J. B.
Claridge, M. J. Rosseinsky, C. J. Kepert, J. Am. Chem. Soc. 2002, 124, 9574, and
references therein; c) Y. H. Kiang, G. B. Gardner, S. Lee, Z. Xu, E. B. Lobkovsky,
J. Am. Chem. Soc. 1999, 121, 8204; d) L. C. Tabares, J. A. R. Navarro, J. M. Salas,
J. Am. Chem. Soc. 2001, 123, 383; e) X. Xu, M. Nieuwenhuyzen, S. L. James,
Angew. Chem. 2002, 114, 790; Angew. Chem. Int. Ed. 2002, 41, 764.
40- a) J. Zhu, X. Bu, P. Feng, G. D. Stucky, J. Am. Chem. Soc. 2000, 122, 11563; b) K.
Barthelet, J. Marrot, D. Riou, G. FQrey, Angew. Chem. 2002, 114, 291; Angew.
Chem. Int. Ed. 2002, 41, 281, and references therein; c) P. Losier, M. J. Zaworotko,
Angew. Chem. 1996, 108, 2957; Angew. Chem. Int. Ed. Engl. 1996, 35, 2779.
41- a) M. J. Zaworotko, Chem. Soc. Rev. 1994, 23, 283; b) C. M. Draznieks, S. Girard,
G. FQrey, J. C. Schon, Z. Cancarevic, M. Jansen, Chem. Eur. J. 2002, 8, 4103, and
references therein; c) A. Hori, A. Akasaka, K. Biradha, S. Sakamoto, K. Yamaguchi,
M. Fujita, Angew. Chem. 2002, 114, 3403; Angew. Chem. Int. Ed. 2002, 41, 3269,
and references therein; d) B. Moulton, J. Lu, R. Hajndl, S. Hariharan, M. J.
Zaworotko, Angew. Chem. 2002, 114, 2945; Angew. Chem. Int. Ed. 2002, 41,
2821; e) Handbook of Porous Solids (Eds.: F. SchRth, K. S.W. Sing, J. Weitkamp),
Wiley-VCH, Weinheim, 2002.
9
42- a) D. Hagrman, P. J. Hagrman, J. Zubieta, Angew. Chem. 1999, 111, 3395; Angew.
Chem. Int. Ed. 1999, 38, 3165; b) L. R. MacGillvray, R. H. Groeneman, J. L.
Atwood, J. Am. Chem. Soc. 1998, 120, 2676; c) N. G. Pschirer, D. M. Ciurtin, M.
D. Smith, U. H. F. Bunz, H. C. zur Loye, Angew. Chem. 2002, 114, 603; Angew.
Chem. Int. Ed. 2002, 41, 583, and references therein.
43- a) L. Carlucci, G. Ciani, D. M. Proserpio, A. Sironi, J. Am. Chem. Soc. 1995, 117,
4562; b) S. ubramanian, M. J. Zaworotko, Angew. Chem. 1995, 107, 2295; Angew.
Chem. Int. Ed. Engl. 1995, 34, 2127.
44- a) Comprehensive Coordination Chemistry, Vol. 5, (Ed.: G. Wilkinson), Pergamon,
Toronto, Canada, 1987; b) R. C. Mehrotra, R. Bohra, Metal Carboxylates, Academic
Press, London, 1983; c) Y. Liao, W. W. Schum, S. Miller, J. Am. Chem. Soc. 2002,
124, 9336; d) V. M. Rao, D. N. Sathyanarayana, H. Manohar, J. Chem. Soc. Dalton
Trans. 1983, 2167; e) G. Davey, F. S. Stephens, J. Chem. Soc. A 1971, 103; f) I.
Goldberg, F. H. Herbstein, Acta Crystallogr. Sect. B 1973, 29, 246.
45- a) R. Kiriyama, Acta Crystallogr. 1954, 7, 482; b) R. Kiriyama, Bull. Chem. Soc.
Jpn. 1962, 35, 1199.
46- C. I. Stalhandske, Acta Chem. Scand. 1969, 23, 1525.
47- J. Hatibarua, G. S. Parry, Acta Crystallogr. Sect. B 1972, 28, 3099, and references
therein.
48- a) B. Kozlevkar, N. Lah, S. Makuc, P. Segedin, F. Pohleven, Acta Chim. Slov.
2000, 47, 421; b) B. Morosin, R. C. Hughes, Z. G. Soos, Acta Crystallogr. Sect. B
1975, 31, 762; c) V. J. Pickardt, Acta Crystallogr. Sect. B 1981, 37, 1753.
49- a) B. K. Koo, Bull. Korean Chem. Soc. 2001, 22, 113; b) J. E. Fiscus, S. Shotwell,
R. C. Layland, M. D. Smith, H. C. zur Loye, U. H. F. Bunz, Chem. Commun. 2001,
2674.
50- S. R. Batten, B. F. Hoskins, B. Moubaraki, K. S. Murray, R. Robson, Chem.
Commun. 2000, 1095.
51- F. A. Cotton, Y. Kim, J. Am. Chem. Soc. 1993, 115, 8511, and references therein.
52- J. Lu,W. T. A. Harrison, A. J. Jacobson, Chem. Commun. 1996, 399.
53- a) C. Cadiou, R. A. Coxell, A. Graham, A. Harrison, M. Helliwell, S. Parsons, R. E.
P.Winpenny, Chem. Commun. 2002, 1106, and references therein; b) D. J. Price, S.
R. Batten, B. Moubaraki, K. S. Murray, Chem. Commun. 2002, 762; c) M. Eshel,
A. Bino, I. Felner, D. C. Johnston, M. Luban, L. L. Miller, Inorg. Chem. 2000, 39,
1376, and references therein; d) J. G. Mao, A. Clearfield, Inorg. Chem. 2002, 41,
2319.
54- a) A. J. Blake, C. M. Grant, S. Parsons, J. M. Rawsons, R. E. P. Winpenny, J. Chem.
Soc. Chem. Commun. 1994, 2363; b) S. P. Watton, P. Fuhrmann, L. E. Pence, A.
Caneschi, A. Cornia, G. L. Abbatti, S. J. Lippard, Angew. Chem. 1997, 109, 2917;
Angew. Chem. Int. Ed. Engl. 1997, 36, 2774.
55- G. Dong, Z. Bing-guang, D. C. Ying, P. Ke-liang, M. Qing-jin, J. Chem. Soc.
Dalton Trans. 2002, 3783.
10
56- a) Y. Laget, C. Hornick, M. Drillon, J. Mater. Chem. 1999, 9, 169; b) S. Yamanaka,
T. Sako, K. Seki, M. Hattori, Solid State Ionics 1992, 53, 527; c) S. Yamanaka, T.
Sako, M. Hattori, Chem. Lett. 1989, 1869.
57- R. Kuhlman, G. L. Schimek, J.W. Kolis, Inorg. Chem. 1999, 38, 194.
58- I. A. Koval, P. Gamez, O. Roubeau, W. L. Driessen, M. Lutz, A. L. Spek, J.
Reedijk, Inorg. Chem. 2003, 42, 868.
59- W. Schmitt, E. Baissa, A. Mandel, C. E. Anson, A. K. Powell, Angew. Chem. 2001,
113, 3689; Angew. Chem. Int. Ed. 2001, 40, 3577.
60- a) L. Brammer, M. D. Burgard, M. D. Eddleston, C. S. Rodger, N. P. Rath, H.
Adams, CrystEngComm 2002, 4, 239; b) L. Brammer, M. D. Burgard, C. S. Rodger,
J. K. Swearingen, N. P. Rath, Chem. Commun. 2001, 2468; c) C. M. Rivas, L.
Brammer, Coord. Chem. Rev., 1999, 183, 43; d) G. R. Desiraju, Crystal
Engineering: The Design of Organic Solids, Elsevier, New York, 1989.
61- G. S. Papaefstathiou, L. R. MacGillvray, Angew. Chem. 2002, 114, 2174; Angew.
Chem. Int. Ed. 2002, 41, 2070.
11
CHAPTER 2
2-1- Antibiotic Drugs
2-1-1- Quinolone
Essential structure of all quinolone (Fig. 2-1) antibiotics: the blue drawn
remainder of R is usually piperazine; if the connection contains fluorine, it is a
fluoroquinolone.
Fig. 2-1: Structure of Quinolone.
The quinolones are divided into generations based on their antibacterial spectrum [1, 2].
The earlier generation agents are, in general, narrower spectrum than the later ones. Generally
the quinolones are grouped by generations by researchers. But there is no standard employed to
determine which drug belongs to which generation. The only universal standard applied is the
grouping of the non-fluorinated drugs found within this class (quinolones) within the first
generation heading. As such there exists a wide variation within the literature dependent upon
the methods employed by the authors. Some researchers group these drugs by patent dates,
some by a specific decade (i.e. 60’s 70’s 80’s etc.) and others by the various structural changes.
The first generation is rarely used today. Nalidixic acid was added to the OEHHA Prop 65 list
as a carcinogen on May 15, 1998 [3]. A number of the 2nd, 3rd and 4th generation drugs have
been removed from clinical practice due to severe toxicity issues or discontinued by their
manufacturers. The drugs most frequently prescribed today consist of Avelox (moxifloxacin),
Cipro (ciprofloxacin), Levaquin (levofloxacin) and to some extent their generic equivalents.
1st generation
cinoxacin (Cinobac) (Removed from clinical use) [4].
flumequine (Flubactin) (Genotoxic carcinogen)(Veterinary use)
nalidixic acid (NegGam, Wintomylon) [4] (Genotoxic carcinogen)
oxolinic acid (Uroxin) (Currently unavailable in the United States)
piromidic acid (Panacid) (Currently unavailable in the United States)
pipemidic acid (Dolcol) (Currently unavailable in the United States)
rosoxacin (Eradacil) (Restricted use, currently unavailable in the United States)
nd
2 generation
The 2nd generation class is sometimes subdivided into "Class 1" and "Class 2" [5].
ciprofloxacin (Ciprobay, Cipro, Ciproxin) [3,5].
enoxacin (Enroxil, Penetrex) [3] (Removed from clinical use)
fleroxacin (Megalone, Roquinol) (Removed from clinical use)
12
lomefloxacin (Maxaquin) [3] (Discontinued in the United States)
nadifloxacin (Acuatim, Nadoxin, Nadixa) (Currently unavailable in the United States)
norfloxacin (Lexinor, Noroxin, Quinabic, Janacin) [3] (restricted use) [6]
ofloxacin (Floxin, Oxaldin, Tarivid) [3] (Discontinued in the United States)
pefloxacin (Peflacine) (Currently unavailable in the United States)
rufloxacin (Uroflox) (Currently unavailable in the United States)
rd
3 generation
Unlike the first and second generation, the third generation is active against streptococci. [5]
Balofloxacin (Baloxin) (Currently unavailable in the United States)
Gatifloxacin (Tequin) (Zymar) (removed from clinical use) [7] Sometimes reported as
4th Generation [5,8]
Grepafloxacin (Raxar) (Removed from clinical use)
Levofloxacin (Cravit, Levaquin) [1,3]
Moxifloxacin (Avelox,Vigamox) [1] (restricted use) [9]. Sometimes reported as 4th
generation [3, 10].
Pazufloxacin (Pasil, Pazucross) (Currently unavailable in the United States)
Sparfloxacin (Zagam) [4] (restricted use), [11].
Temafloxacin (Omniflox) (Removed from clinical use) [12]
Tosufloxacin (Ozex, Tosacin) (Currently unavailable in the United States)
th
4 generation
Clinafloxacin [6] (Currently unavailable in the United States)
Gemifloxacin (Factive)
Sitafloxacin (Gracevit) (Currently unavailable in the United States)
Trovafloxacin (Trovan) (Removed from clinical use) [4,6]
Prulifloxacin (Quisnon) (Currently unavailable in the United States)
The quinolones also referred to as fluoroquinolones are a family of synthetic broad-spectrum
antibiotics. The term quinolone(s) refers to potent synthetic chemotherapeutic antibacterials
[1,2] the first generation of which was derived from an attempt to create a synthetic form of
chloroquine, which was used to treat malaria during World War II. Hans Andersag discovered
chloroquine, in 1934 at Bayer I.G. Farbenindustrie A.G. laboratories in Eberfeld, Germany. The
first generation of the quinolones begins with the introduction of nalidixic acid in 1962 for
treatment of urinary tract infections in humans [13]. Nalidixic acid was discovered by George
Lesher and coworkers in a distillate during an attempt at chloroquine synthesis [14]. They
prevent bacterial DNA from unwinding and duplicating [15]. Recent evidence has shown that
topoisomerase II is also a target for a variety of quinolone-based drugs. Thus far, most of the
compounds that show high activity against the eukaryotic type II enzyme contain aromatic
substituents at their C-7 positions [16]. Quinolones in comparison to other antibiotic classes
have the highest risk of causing colonisation with MRSA and C Difficile. A general avoidance
of fluoroquinolones is recommended based on the available evidence and clinical guidelines
[17-19]. The parent of the quinolone (aka fluoroquinolone) class is nalidixic acid. The majority
of quinolones in clinical use belong to the subset of fluoroquinolones, which have a fluorine
atom attached to the central ring system, typically at the 6-position or C-7 position. The
effectiveness of drugs depends on their binding ability [21-24]. Ciprofloxacin (CPF) and
13
norfloxacin (NRF) belong to fluoroquinolones (FQ), which are bacteriostatic at low
concentration and bactericidal at high concentrations. They are highly active against most
Gram-negative pathogens including Pseudomonas aeruginosa and the Enterobacteriaceae.
Fluoroquinolones are used to treat upper and lower respiratory infections, gonorrhea, bacterial
gastroenteritis, skin and soft tissue infections and both uncomplicated and complicated urinary
tract infections, especially those caused by Gram-negative than Gram-positive infections.
Fluoroquinolones are often used for genitourinary infections; in general they are recommended
only after other antibiotic regimes have failed. However, for serious acute cases of
pyelonephritis or bacterial prostatitis where the patient may need to be hospitalised
fluoroquinolones are recommended as first line therapy [10]. Prostatitis has been termed "the
waste basket of clinical ignorance" by prominent Stanford University Urologist Dr. Thomas
Stamey. Campbell's Urology, the urologist's most authoritative reference text, identifies only
about 5% of all patients with prostatitis as having bacterial prostatitis which can be "cured" at
least in the short term by antibiotics. In other words, 95% of men with prostatitis have little hope
for a cure with antibiotics alone since they don't actually have any identifiable bacterial infection
[25]. Fluoroquinolones (FQs) are a class of relatively new and entirely man-made, non-steroidal
antibiotics/antibacterials. They are used to treat infection in many parts of the body by killing the
harmful bacteria or preventing their growth. Norfloxacin, the first FQ, was synthesized by
converting nalidixic acid into a quinolone structure, adding a fluorine atom and a piperazine
ring. Other first generation FQs introduced in the 1980s included ciprofloxacin and ofloxacin
Ofloxacin is a racemic mixture and its active form is the (−) S isomer, levofloxacin. FQs are
pharmacologically superior to nalidixic acid because they exhibit broader activity against Gram
(−) and Gram (+) bacteria, less protein binding, higher drug tolerance, lower toxicity, and longer
half-life. In Europe and other parts of the world, these three FQs are still heavily used in many
human and animal applications. Ciprofloxacin, in its hydrochloride form, is perhaps the most
popular FQ and it is one of the top 20 prescription drugs in Canada. This drug has also received
considerable attention lately in the USA where it has been approved as one type of antibiotic for
the treatment of the inhaled form of anthrax [26]. Quinolones are synthetic antibiotics whose
action is based on their anti-DNA activity. Nalidix acid was the first quinolones approved on
1963, by Food and Drug Administration (FDA) for the treatment of urinary tract infections.
Quinolones are widely used till nowadays in human and in veterinary medicine, due to their
safety with good tolerance and broad antibacterial spectrum. Fluoroquinolones belong to the
second generation of quinolones and their characteristic is the greater effectiveness against both
Gram-negative and Gram-positive pathogens that are resistant to other antibacterials [27]. The
fluoroquinolone group of antimicrobial agents has a broad antibacterial spectrum and is active
against most Gram-negative and many Grampositive bacteria [28]. The pharmacokinetics of
these drugs has been extensively studied across a range of subjects including healthy young
volunteers, the elderly, patients with renal impairment, and patients with liver disease. The
fluoroquinolone group exhibits excellent oral bioavailability, extensive tissue penetration, low
protein binding, and a long elimination half-life. There are, however, significant differences
between individual fluoroquinolones in their oral bioavailability, route of elimination,
elimination half life, and drug interactions. This review will compare and contrast the
pharmacokinetics of some of the quinolone group, specifically pefloxacin, enoxacin,
14
norfloxacin (Fig. 2-2), ciprofloxacin (Fig. 2-3), ofloxacin (Fig. 2-4), fleroxacin, and
lomefloxacin.
Fig. 0-2: Structure of norfloxacin.
Fig. 0-3: Structure of ciprofloxacin.
Fig. 0-4: Structure of Ofloxacin.
The quinolone antibiotics are synthetic antimicrobial agents with a broad spectrum of
activity widely used in human and veterinary medicine. Extensive use of antibiotics in
veterinarian medicine and medicated feed play a crucial role in intensive animal production in
food-producing animals and farmed fish such as prawn, salmon and catfish. It leads to a
significant increase in antibiotic resistance and allergic reactions, having therefore important
consequences on public health. Moreover, quinolone-induced acute arthropathy has been
15
observed in several animal species. Although severe cases of arthropathy have been observed
only rarely in humans, incidents of transient arthralgia have also been reported. These
observations have precluded the use of quinolones in childrenand pregnant women. To
safeguard human health, the European Union set a Maximum Residue Limits (MRLs) of 30
ppb for the sum of enrofloxacin and its metabolite, ciprofloxacin, in muscle, kidney and liver
[29]. The basic pharmacophore, or active structure, of the fluoroquinolone class is based upon
the quinoline ring system [30]. The addition of the fluorine atom at C6 is what distinguishes the
successive generations, fluoroquinolones, from the first generation, quinolones. It has since been
demonstrated that the addition of the C6 fluorine atom is not a necessary requirement for the
antibacterial activity of this class (circa 1997) [31]. Various substitutions made to the quinoline
ring resulted in the development of numerous fluoroquinolone drugs that we see today. Each
substitution is associated with a number of specific adverse reactions, as well as increased
activity against bacterial infections, where as the quinoline ring, in and of itself, has been
associated with severe and even fatal adverse reactions [32]. Quinolones and fluoroquinolones
are chemotherapeutic bactericidal drugs, eradicating bacteria by interfering with DNA
replication. The other antibiotics used today, (e.g., tetracyclines, lincomycin, erythromycin, and
chloramphenicol) do not interact with components of eukaryotic ribosomal particle and thus
have proven not to be toxic to eukaryotes, [33] as opposed to the fluoroquinolone class of drugs.
Safer drugs used to treat bacterial infections, such as penicillins and cephalosporins, inhibit cell
wall biosynthesis, thereby causing bacterial cell death, as opposed to the interference with DNA
replication as seen within the fluoroquinolone class of drugs. Quinolones are synthetic
chemotherapeutic agents which have a broad spectrum of antimicrobial activity as well as a
unique mechanism of action resulting in inhibition of bacterial DNA gyrase and topoisomerase
IV. Quinolones inhibit the bacterial DNA gyrase or the topoisomerase IV enzyme, thereby
inhibiting DNA replication and transcription. Quinolones can enter cells easily via porins and
therefore are often used to treat intracellular pathogens such as Legionella pneumophila and
Mycoplasma pneumoniae. For many gram-negative bacteria DNA gyrase is the target, whereas
topoisomerase IV is the target for many gram-positive bacteria. It is believed that eukaryotic
cells do not contain DNA gyrase or topoisomerase IV. However, there is debate concerning
whether the quinolones still have such an adverse effect on the DNA of healthy cells, in the
manner described above, hence contributing to their adverse safety profile. This class has been
shown to damage mitochondrial DNA [34-41]. Norfloxacin is a synthetic chemotherapeutic
agent [42, 43] occasionally used to treat common as well as complicated urinary tract infections
[44]. It is sold under various brand names with the most common being Noroxin. In form of
ophthalmic solutions it is known as Chibroxin. Norfloxacin is a second generation synthetic
fluoroquinolone (quinolone) developed by Kyorin Seiyaku K.K. (Kyorin) [45]. The licensed
uses for norfloxacin are quite limited as norfloxacin is to be considered a drug of last resort
when all other antibiotics have failed. There are currently only three approved uses in the adult
population [46] (one of which is restricted [47] and the other ineffective due to bacterial
resistance. Chibroxin [48] (ophthalmic) is approved use in children older than one year of age.
Norfloxacin interacts with a number of other drugs, as well as a number of herbal and natural
supplements. Such interactions increase the risk of anticoagulation and the formation of nonabsorbable complexes, as well as increasing the risk of toxicity [49].
16
Norfloxacin is associated with a number of serious and life threatening adverse
reactions as well as spontaneous tendon ruptures and irreversible peripheral neuropathy. Such
reactions may manifest long after therapy had been completed and in severe cases may result in
lifelong disabilities. Hepatoxicity resulting in fatalities has also been reported with the use of
norfloxacin Norfloxacin (NFX) is a member of fluoroquinolones and it is chemically named as
1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(piperazin-1-yl)quinoline-3-carboxylic acid. It is the first
choice drug for the treatment of diseases caused by Campylobacter, E. coli, Salmonella, and
Shigella and V. colera. It is used for the treatment of gonorrhoea as well as eye and urinary tract
infection [50]. The antibiotic (Norfloxacin) is one of theantibiotics commonly used to treat
either genitourinary tract or prostate infections, and also gonorrhea. Unfortunately, though
Norfloxacin has frequent use-limiting side effects including headache, abdominal pain,
vomiting and systemic toxicity. For this reason, our research effort turned to the study of the
antimicrobial activity of essential oils in a view to developing safer drugs. It is worthwhile
remembering that the clinical use of essential oils against systemic infections has been strongly
hindered by the fact that they are poorly absorbed by the human intestine and exhibit a ‘‘weak’’
action compared to commercial or synthetic antibiotics. Nevertheless, in spite of these negative
aspects, many essential oils have been produced for treating localized bacterial infections.What
is more, the activity of essential oils both in vitro and in vivo has been the subject of a number of
scientific papers. Many of the essential oils studied have been proven to be efficient only at
elevated concentrations when their microbicidal action turns out to be more pronounced. For
this reason, some synergistic combinations among different essential oils have been recently
studied in a view to increasing their antibacterial action without additionally increasing their
concentration [51]. Norfloxacin is a broad-spectrum antibiotic that is active against both Grampositive and Gram-negative bacteria. It functions by inhibiting DNA gyrase, a type II
topoisomerase, and topoisomerase IV [52] enzymes necessary to separate bacterial DNA,
thereby inhibiting cell division. This mechanism can also affect mammalian cell replication. In
particular, some congeners of this drug family (for example those that contain the C-8 fluorine)
[53] display high activity not only against bacterial topoisomerases, but also against eukaryotic
topoisomerases and are toxic to cultured mammalian cells and in vivo tumor models [54].
Although quinolones are highly toxic to mammalian cells in culture, its mechanism of cytotoxic
action is not known. Quinolone induced DNA damage was first reported in 1986 (Hussy et al.)
[55]. Recent studies have demonstrated a correlation between mammalian cell cytotoxicity of
the quinolones and the induction of micronuclei. [56]. As such some fluoroquinolones,
including Norfloxacin, may cause injury to the chromosome of eukaryotic cells [57]. There
continues to be considerable debate as to whether or not this DNA damage is to be considered
one of the mechanisms of action concerning the severe adverse reactions experienced by some
patients following fluoroquinolone therapy [58].
Ciprofloxacin [1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(piperazinyl) quinolone-3carboxylic acid] and norfloxacin [1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7(piperazin-1yl)quinoline-3-carboxylic acid, belongs to the quinolones which are synthetic antibiotics,
chemically related to nalidixic acid. These drugs form a group of antimicrobial agents with
different chemical structures and spectra of activity. Almost all of the recent clinically useful
quinolones bear afluorine atom in the C-6 position and thus, these antibacterial agents are called
17
fluoroquinolones. These quinolones are effectives against gram-positive and gram-negative
bacteria through inhibition of their NAD gyrase, a critical enzyme to bacterial chromosome
replication. It is used in a wide range of gastrointestinal, urinary and respiratory tract infections;
ocular and skin infections as well as in patients with intraabdominal infections in combination
with antianaerobic agents recently, CF significance as effective drug in Bacillus anthracis
infection treatment essentially increased, because of bacteriological (anthrax) terrorists’ attack
threats [59]. Ciprofloxacin is a drug used to treat bacterial infections. It is a second generation
fluoroquinolone antibacterial. It kills bacteria by interfering with the enzymes that cause DNA
to rewind after being copied, which stops DNA and protein synthesis. Ciprofloxacin is marketed
worldwide with over three hundred different brand names. In the United States, Canada and the
UK, it is marketed as Ciloxan, Cipro, Cipro XR, Cipro XL Ciproxin and, most recently,
Proquin. In Mexico it is available over the counter and marketed under the names Ciproflox or
Ciprofloxacino. In Ecuador it is available and marketed under the name Cidrax. In Nigeria it is
sold as Ciprotab while in Bangladesh it is marketed as tablets and microcapsules for suspension
by numerous companies, one of which is by Edruc Limited as Cipron. Additionally,
ciprofloxacin is available as a generic drug under a variety of different brand names and is also
available for limited use in veterinary medicine [60]. Ciprofloxacin is a broad-spectrum
antibiotic that is active against both Gram-positive and Gram-negative bacteria. It functions by
inhibiting DNA gyrase, a type II topoisomerase, and topoisomerase IV, enzymes necessary to
separate bacterial DNA, thereby inhibiting cell division [61]. This mechanism can also affect
mammalian cell replication. In particular, some congeners of this drug family (for example
those that contain the C-8 fluorine) [62] display high activity not only against bacterial
topoisomerases, but also against eukaryotic topoisomerases and are toxic to cultured
mammalian cells and in vivo tumor models [63]. Although quinolones are highly toxic to
mammalian cells in culture, its mechanism of cytotoxic action is not known. Quinolone induced
DNA damage was first reported in 1986 (Hussy et al.) [64]. Recent studies have demonstrated a
correlation between mammalian cell cytotoxicity of the quinolones and the induction of
micronuclei [65]. As such some fluoroquinolones may cause injury to the chromosome of
eukaryotic cells [66]. There continues to be debate as to whether or not this DNA damage is to
be considered one of the mechanisms of action concerning the severe adverse reactions
experienced by some patients following fluoroquinolone therapy [67]. Aluminium (Al3+), the
metal with the strongest complex-forming ability towards FQ, yields FQ_/Al complexes with a
3:1 stoichiometry that are highly stable in aqueous solution. The hydrochlorides of 3:1
aluminium complexes of norfloxacin and ciprofloxacin, (HCl/NORX)3Al and (HCl/ CIPX)3Al),
respectively, were isolated as stable solids in our laboratory. These compounds, NORX/Al and
CIPX/Al, exhibit high aqueous solubility under conditions in which FQ are almost insoluble.
Their biological and physicochemical properties of pharmaceutical interest have been already
reported. A neutral ophthalmic formulation has been successfully developed with CIPX-Al, as
well as solid formulations for oral administration. Some reports have described a reduction in
oral bioavailability and antibacterial activity of FQ in presence of an excess of polyvalent metal
cations such as Al3+ or Mg2+, i.e. a molar excess of 4300-fold of Al3+ with respect to CIPX
yielded a 50% reduction in the bactericidal rate. However, data available clearly demonstrate
that limited amounts of Al3+ do not affect the ability of FQ to pass through a biological
18
membrane, the oral bioavailability or antimicrobial activity (expressed as MIC values). In this
context, only few studies have been conducted to examine how the interaction antibiotic-metal
affects the antimicrobial activity of FQ [68]. The binding of several lanthanide(III) ions to
anthracycline antitumor antibiotics daunomycin and adriamycin in methanol and aqueous
solutions has been studied by means of optical and 2D NMR (COSY, TOCSY, and EXSY)
techniques [69]. These results indicate that a 1:1 Yb3+ drug complex is the predominant
complex at a metaltoligand ratio <10 with slightly higher proton activities, e.g., pH 4-5 in an
aqueous solution. In the presence of a base, a 1:2 or 1:3 Yb3+ drug complex can be formed (Fig.
0-5). In addition, a 2:1 complex is formed when the metal-to-drug ratio is >25. These Yb3+ drug
complexes undergo slow chemical exchange with each other relative to the NMR time scale.
Therefore, 1D and 2D magnetization transfer experiments can be utilized for the assignment of
the isotropically shifted signals arising from the drug nuclei in the various paramagnetic
complexes. The spin-lattice (T1) relaxation times and solution magnetic susceptibilities of these
Yb3+ drug complexes confirmed the binding of the metal ion to 11,12-a-ketophenolate in all the
complexes (except the second Yb3+ in the 2:1 complex which binds to the 5,6-a-ketophenolate).
Several other lanthanide(III) ions Pr3+, Eu3+, and Dy3+ show similar binding properties to
daunomycin based on optical and NMR studies. The binding of Yb3+ to daunomycin has a
profound effect on the reduction potential of the drug, showing a decrease in the potential by
150 mV upon addition of 1 equiv of Yb3+ to the drug solution. This observation indicates that
metal ions must play a significant role in the action of this family of drugs in vivo iprofloxacin.
Fig. 0-1: Yb3+ drug complex.
The interaction of magnesium, calcium and barium perchlorate with ciprofloxacin (CIP)
and norfloxacin (NOR) has been investigated [69]. Elemental analysis, FTIR, electrical
conductivity and thermal analysis have been used to characterize the isolated complexes. The
results support the formation of complexes of the formula [M(NOR)2](ClO4)2.xH2O and
[M(CIP)2](ClO4)2.xH2O (M = Mg+2, Ca+2 and Ba+2) (Fig. 2-6). The FTIR spectra of the isolated
complexes suggest that CIP and NOR act as bidentate ligands through the ring carbonyl oxygen
atom and one of the oxygen atoms of the carboxylic group.
19
Fig. 2-6: Structure of [M(NOR)2](ClO4)2.xH2O
Nine new metal complexes of the quinolone antibacterial agent N-propyl-norfloxacin, prnorfloxacin, with VO2+, Mn2+, Fe3+, Co2+, Ni2+, Zn2+, MoO2, Cd2+ and UO2 have been prepared
and characterized with physicochemical and spectroscopic techniques while molecular
mechanics calculations for Fe3+, VO2+ and MoO2 complexes have been performed [70]. In all
complexes, pr-norfloxacin acts as a bidentate deprotonated ligand bound to the metal through
the pyridone and one carboxylate oxygen atoms. All complexes are six-coordinate with slightly
distorted octahedral geometry. For the complex VO(N-propyl-norfloxacinato)2(H2O) the axial
position, trans to the vanadyl oxygen, is occupied by one pyridone oxygen atom. The
investigation of the interaction of the complexes with calf-thymus DNA has been performed
with diverse spectroscopic techniques and has shown that the complexes can be bound to calfthymus DNA resulting to a DNA transition. The antimicrobial activity of the complexes has
been tested on three different microorganisms. The complexes show equal or decreased
biological activity in comparison to the free pr-norfloxacin except UO2(pr-norf)2 (Fig. 0-7)
which shows better inhibition against S. aureus.
20
Fig. 0-2: Structure UO2(pr-norf)2
The investigation of the new structures of Ag(I), Cu(II) and Au(III) complexes,
[Ag2(Nor)2](NO3)2 (Fig. 2-8), [Cu(Nor)2(H2O)2]SO4·5H2O and [Au(Nor)2(H2O)2]Cl3
(Fig. 2-9) (where, Nor = norfloxacin) was done during the reaction of silver(I),
copper(II) and gold(III) ions with norfloxacin drug ligand [71]. Elemental analysis of
CHN, infrared, electronic, 1H NMR and mass spectra, as well as thermo gravimetric
analysis (TG and DTG) and conductivity measurements have been used to characterize
the isolated complexes. The powder XRD studies confirm the amorphous nature of the
complexes. The norfloxacin ligand is coordinated to Ag(I) and Au(III) ions as a neutral
monodentate chelating through the N atom of piperidyl ring, but the copper(II) complex
is coordinated through the carbonyl oxygen atom (quinolone group) and the oxygen
atom of the carboxylic group. The norfloxacin and their metal complexes have been
biologically tested, which resulted in norfloxacin complexes showing moderate activity
against the gram positive and gram negative bacteria as well as against fungi.
21
Fig. 0-3: Structure of [Ag2(Nor)2](NO3)2
Fig. 0-4: Structure of [Au(Nor)2 (H2O)2]Cl3
22
Transport of organic ligands into bacterial cells can be facilitated by the formation of
metal complexes. Hence, the bismuth complex of norfloxacin was synthesized [72] (Fig.
0-10). It was characterized by UV, IR, DSC, atomic absorption spectroscopy, KarlFischer titrametry and elemental analysis. The complex was found to possess metal to
ligand ratio of 1:4. It has been observed that complexation between bismuth ions and
norfloxacin takes place above pH 7. The Solubility of NBC was found to be more than
that of norlfoxacin. Agar diffusion method was used for antibacterial activity. BNC was
found to possess better activity (lesser MIC value) than that of norfloxacin as well as
bismuth citrate and norfloxacin physical admixture. It was concluded that BNC can be a
better alternative to norfloxacin as an antibacterial agent.
Fig. 0-5: Bismuth complex of norfloxacin.
Efficient fragmentation analysis is done through two algorithms, namely binary and
semantic nets. Interpretation process was performed via association between valid
molecular fragments and each weight loss [73]. The procedure was carried out using
semantic net algorithm as a function of temperature. The automation for interpreting
chemical processes was performed in order to create the inference method to determine
thermogravimetric analysis. The actual expert system can, in principle, generate a large
number of decomposition routes in which may be not adequately analyzed by humans
due to their inherent limitations. The advantage of this approach can be attributed to its
efficient error minimization for each weight loss and global process. However,
Analgesics Drugs there are disadvantages. For example, for the particular case of
multiple steps TGA in which there are poor resolved steps the actual expert system can
use the human inference or keeping evaluating the decomposition but considering the
analysis through the differential thermal analysis (DTG) curve. In this case each weight
loss in TG curve is determined by the difference between two local maximum in the
DTG curve. Similarly, the analysis of polymers cannot be performed with the actual
expert system in its present form. One of the reasons is attributed to the unresolved
empirical formula for the polymer (number of monomers). The system needs empirical
formula definitions to obtain a set of valid molecular fragments. In this case, it is
23
necessary a new implementation to increase a distribution of the composition to be used
for polymers analysis. The expert system may be also applied to the case of parallel
decomposition reactions through the combination of valid fragments in only one weight
loss. However, in its present form such analyses are not implemented. In addition,
another limitation is concerned with the determination of fractional stequiometric
indexes. Finally, the validation tests showed the viability of using the proposed
methodology for interpreting thermogravimetric data. In addition, the computational
cost is compatible with microcomputers. Accordingly, the system may be considered as
a useful tool for the experimentalist in many thermogravimetric analyses. A new
spectrofluorimetric method was developed for the determination of trace amounts of
lecithin [74]. NF can form a binary complex with Tb3+, which emits a peak at 545 nm.
Lecithin can combine with this NF–Tb3+ complex because of the phosphate radical, and
can remarkably reduce its fluorescence intensity at k =545 nm. The reduction in the
fluorescence intensity of the Tb3+ ion is proportional to the concentration of lecithin.
This method has been successfully applied to the determination of serum samples. The
interactions of manganese acetate, ferric chloride and cobalt sulphate with norfloxacin
(NOR) in acetone or methanol were studied [75]. The isolated solid complexes were
characterized by elemental analysis, infrared, electronic, mass spectra and thermal
analysis. The results support the formation of complexes of the formula
[Fe(NOR)3]Cl3.12H2O (Fig. 2-11) and [M(NOR)2]X2.8H2O (M=Mn(II) or Co(II) and
X= (CH3COO-) or SO42- ) (Fig. 0-12). The infrared spectra of the isolated solid
complexes suggested, indicated that NOR act as bidentate ligands through one of the
oxygen atoms of the carboxylic group and the ring carbonyl oxygen atom. The
interpretation, mathematical analysis and evaluation of kinetic parameters of
thermogravimetric (TGA) and its differential (DTG), such as entropy of activation, preexponential factors, activation energy evaluated by using Coats–Redfern and Horowitz–
Metzger equations for two complexes are carried out. General mechanisms describing
the decomposition of the solid complexes are suggested.
Fig. 0-6: Structure of [M(NOR)2]X2.8H2O
24
Fig. 0-7: Stucture of [Fe(NOR)3]Cl3.12H2O
Simple, rapid, reliable, and sensitive spectrofluorometric methods were developed for
the determination of eight quinolone antibacterials namely ciprofloxacin, norfloxacin,
lomefloxacin, difloxacin, amifloxacin, pefloxacin, ofloxacin, and nalidixic acid [76].
The methods depend on the chelation of each of the studied drugs with zirconium,
molybdenum, vanadium or tungsten to produce fluorescent chelates. Different factors
affecting the relative fluorescence intensity of the resulting chelates were studied and
optimised. At the optimum reaction conditions, the drug_/metal chelates showed
excitation maxima ranging from 274 to 295 nm and emission maxima ranging from 409
to 495 nm. The chelates were found to be stable at room temperature for 2 days and
show good stability upon increasing temperature to 50 oC for about 1 h. Rectilinear
calibration graphs were obtained in the range of 10-60 ng.ml-1 for each of the
investigated drugs and the limits of detection and quantitation ranged from 1.214 to
2.046 and from 4.047 to 6.819 ng ml-1, respectively. The molar ratios of the formed
chelates were determined by Job’s method and their association constants were also
calculated. The developed methods were applied successfully for the determination of
the studied drugs in their pharmaceutical dosage forms with a good precision and
25
accuracy compared to official and reported methods as revealed by t - and F-tests. They
were also applied for the determination of studied drugs in spiked urine and plasma
samples. A reversed flow injection colorimetric procedure for determining iron(III) at
the mg level was proposed [77]. It is based on the reaction between iron(III) with
norfloxacin (NRF) in 0.07 mol l-1 ammonium sulfate solution, resulting in an intense
yellow complex with a suitable absorption at 435 nm. Optimum conditions for
determining iron(III) were investigated by univariate method. The method involved
injection of a 150 ml of 0.04% w/v colorimetric reagent solution into a merged streams
of sample and/or standard solution containing iron(III) and 0.07 mol l-1 ammonium
sulfate in sulfuric acid (pH 3.5) solution which was then passed through a single bead
string reactor. Subsequently the absorbance as peak height was monitored at 435 nm.
Beer’s law obeyed over the range of 0.2-1.4 mg ml-1 iron(III). The method has been
applied to the determination of total iron in water samples digested with HNO3:H2O2
(1:9 v/v). Detection limit (3s) was 0.01 mg ml-1 the sample through of 86 h-1 and the
coefficient of variation of 1.77% (n=12) for 1 mg ml-1 Fe(III) were achieved with the
recovery of the spiked Fe(III) of 92.6-99.8%. Three novel complexes of norfloxacin
(abbreviated as NFL), [M(NFL)iH2O)2]Cl3.6H20, (M =Fe, Co), and [Zn(NFL)2]CI2·
7H2O, have been prepared [78]. The compounds were characterized by IR, UV-Vis,
NMR spectra, molar conductivity, and elemental analyses. In all of the complexes, the
ligand NFL was coordinated through two carboxyl oxygen atoms. Octahedral and
tetrahegon geometries have been proposed for Fe(III)-, Co(II)-complexes and Zn(II)complex, respectively. In vitro test of susceptibility of Fe(III)- and Zn(II)-complexes
showed stronger activity than that of norfloxacin against G(-) E.Coli and Bacillus
dysenteriae bacteria. Norfioxacin, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)
-3-quinoline carboxylic acid (NORH), reacts with aluminium(III) ion forming the
strongly fluorescent complex [Al(HNOR)]3+, in slightly acidic medium [79]. The
complex shows maximum emission at 440 nm with excitation at 320 nm. The
fluorescence intensity is enhanced upon addition of 0.5% sodium dodecylsulphate.
Fluorescence properties of the Al-NOR complex were used for the direct determination
of trace amounts of NOR in serum. The linear dependence of fluorescence intensity on
NOR concentration, at a NOR to Al concentration ratio of 1: 10, was found in the
concentration range 0.001-2 µg/ ml NOR with a detection limit of 0.1 ng/ ml. The
ability of aluminium (III) ion to form complexes with NOR was investigated by
titrations in 0.1 M Liel medium, using a glass electrode, at 298 K, in the concentration
range: 2x10-4 ≤ [Al] ≤ 8x10-4; 5x10-4 ≤ [NOR] ≤ 9x10-4 mol/dm3; 2.8≤ pH ≤ 8.3. The
experimental data were explained by the following complexes and their respective
stability constants, log (β ± α): [Al(HNOR)], (14.60±0.05); [Al(NOR)], (8.83 ±0.08);
[Al(OH)3(NOR)], ( -14.9±0.1), as well as several pure hydrolytic complexes of Al3+.
The structure of the [Al(HNOR)] complex is discussed, with respect to its fluorescence
properties. The dissociation and the complexation behaviours of four f1uoroquinolone
antibiotics have been studied [80]. The acid dissociation constants of ciprofloxacin,
Enoxacin, norfloxacin and ofloxacin were determined by conventional potentiometric
and conductometric techniques. Increasing the Hammett substituent constant, the pKa
26
values were decreased. The absorption of floroquinolones in the intestinal tract are
probably transported by pH-dependent mechanisms. It has been described a
spectrophotometric study on the interaction between norfloxacin (NFX) and metal ions
(AI3+, Mg2+ and Ca2+). Two buffers of pH 3.6 and 8.8 were used [81]. A shift in
absorption maximum was observed and the stoichiometry of the complex was
determined using the Job and molar ratio methods. The ratios were NFX: Al3+, 2: 1 and
3: 1 for the NFX: Mg2+ complex. The formation of a complex with Al3+ enhanced the
water solubility of the drug. Microbiological studies indicated decreased activity of
norfloxacin in the presence of metal ions. Seven members (ciprofloxacin, enrofloxacin,
norfloxacin, ofloxacin, lomefloxacin, pipemidic acid, and flumequine) of the popular
fluoroquinolone antibacterial agents (FQs) were found to adsorb strongly to goethite
with 50–76% of the added FQ adsorbed under the experimental conditions [82]. The
adsorption isotherms fitted well to the Langmuir model. Adsorption was accompanied
by slow oxidation of the FQs (except for flumequine) by goethite yielding a range of
hydroxylated and dealkylated products. The oxidation kinetics showed different stages
in reaction rate, mostly likely caused by accumulation of Fe(II) species on the oxide
surface that slowed the reaction. Structurally related amines 1-phenylpiperazine, Nphenylmorpholine, aniline, and N,N-dimethylaniline were found to be oxidized by
goethite without significant adsorption. The results strongly indicate that the carboxylic
group of FQs is critical for adsorption while the piperazine ring is susceptible to
oxidation. A radical mechanism is proposed for the oxidation of FQs by goethite which
involves formation of a surface complex between the FQ and surface-bound Fe(III)
through adsorption, and initial oxidation at the piperazinyl N1 atom to form radical
intermediates that ultimately lead to the final products. This study indicates that Fe
oxides in aquatic sediments may well play an important role in the natural attenuation of
fluoroquinolone antibacterial agents. A complex of magnesium(II) with the formula
[Mg2(H2O)6(nfH)2]Cl4 .4H2O was isolated by the hydrothermal reaction [83]. It can be
described as a 2:2 dimer in which the two magnesium ions are bridged by two oxygen
atoms from carboxylate groups of the two norfloxacin molecules. Each magnesium ion
is octahedrally coordinated with the oxygen atom of the quinolone carbonyl (Mg(1)O(1)=/1.997(2) A° ), one of the two oxygen atoms of the carboxylate (Mg(1)-O(2) =
2.084(2), Mg(1)-O(2A)=/2.116(2) A° ) and water molecules. The coordination mode of
carboxylate can be considered as a monodentate bridging type. A calcium complex,
[Ca2(Cl)(nfH)6]Cl3.10H2O wasalso isolated by the hydrothermal reaction [84]. This
complex is also a dimer, but the bridging group is a chloride ion. The coordination
geometry around each calcium ion can best be described as a distorted pentagonal
bipyramid. Three norfloxacin molecules act in a bidentate coordination mode through
the oxygen atom of the quinolone carbonyl (Ca(1)-O=/2.384(2)-/2.413(2) A°) and one
of the two oxygen atoms in the carboxylate moiety (Ca(1)-O=/2.383(3)-/2.395(3) A°
).The chloride ion completes the seven-coordination around the calcium (Ca(1)Cl(1)=/2.862(9) A°). The crystal structure and characterization of the mixed ligand
complex of copper(I), triphenyl phosphine and nfH, [Cu(PPh3)2(nfH)]ClO4, were
published [85]. The copper ion displays a rather distorted tetrahedral geometry, being
27
linked to two nfH oxygens (Cu(1)-O(2)=/2.0763(18), Cu(1)-/O(1)=2.074(2) A°) and
two phosphorus atoms of triphenylphosphine ligand (Cu(1)-/P(2)=/2.2389(8), Cu(1)/P(4)=/2.2472(8)A°). Two zinc/norfloxacin complexes, [Zn(nf)2].4H2O and
[Zn(H2O)2(nfH)2](NO3)2 were isolated by hydrothermal synthesis [86]. The X-ray
crystal structure of the first complex revealed that two nf anions are coordinated to the
metal through ring carbonyl (Zn(1)-O(3)=2.095(3) A°) and one of the carboxylate
oxygens (Zn(1)-O(2)=2.070(3) A°). Interestingly, the apical positions are occupied by
two nitrogen atoms of piperazine rings (Zn(1)-N(1A)=2.253(3) A°), resulting in the
formation of a 2-D square grid with a nanosized hydrophobic tube cavity, that could be
very useful for host/guest chemistry. In the second complex, the chelate bonding of the
quinolone oxygen atoms to the metal is similar as in the first complex (Zn(1)O(6)=2.057(3), Zn(1)-O(5)=2.028(3) A°), but the apical positions are occupied by two
water molecules (Zn(1)-/O(3)=2.160(4)). The authors suggest that in a neutral or weakly
basic solution, the nitrogen atom of the piperazine ring can take part in the coordination,
while in the weakly acidic solution, this nitrogen is protonated and loses its coordination
capacity. Authors also reported that both complexes show strong blue fluorescent
emission and could be used as advanced materials for blue-light emitting diode devices.
Four chloride ions are coordinated to the copper(II) ion, forming a rather distorted
tetrahedron in(nfH3)(nfH2)[CuCl4]Cl.H2O [86]. There are two nonequivalent
norfloxacin molecules in the asymmetric unit. In the first, the carbonyl O(1) and
piperazine nitrogen N(24) are both protonated. In the second, only N(24) is protonated.
There are distinctive layers of quinolone molecules in the structure, and the distances
between aromatic rings in the neighboring layers are around 3.5 A°; thus, interactions
between
p-electronic
systems
are
possible.
The
zinc
compound
(nfH3)(nfH2)[ZnCl4]Cl.H2O [86] is isotypic to the copper/norfloxacin compound. The
zinc compound of cfH with the formula (cfH3)[ZnCl4].H2O [87] is also very similar to
the zinc compound of norfloxacin. There are distinctive layers ofquinolone molecules in
the structure which are crosslinked through extensive hydrogen bonding. The
inspections of the bond lengths in the isolated ionic type complexes have revealed the
following facts:
The quinolone molecules could be mono- or doubly protonated.
In monoprotonated species only the terminal nitrogen atom of piperazine ring is
protonated.
In doubly protonated species additionally the ring carbonyl oxygen is
protonated. If this is the case, this carbon/oxygen bond is substantially
lengthened (1.30-1.33 A°).
A new class of surfactant–cobalt(III) complex ions of the type, cis[Co(X)2(C14H29NH2)Cl]2+ (where X= ethylenediamine (en), or 2,2'-bipyridyl (bpy), or
1,10-phenanthroline
(phen))
and
cis-[Co(trien)
(C14H29NH2)Cl]2+
(trien=triethylenetetramine) were synthesized and characterized by IR, NMR, UV–
visible electronic absorption spectra, elemental analysis and metal analysis [88]. The
critical micelle concentration (CMC) values of these surfactant–cobalt(III) complexes in
aqueous solution were obtained from conductance measurements. Specific conductivity
data (at 298, 308, 318 and 328 K) served for the evaluation of the temperatureInternational Science Congress Association
28
dependent CMC and the thermodynamics of micellization (ΔG0m, ΔH0m and ΔS0m).
Interactions between calf thymus DNA and the surfactant–cobalt(III) complexes in
aqueous solution have been investigated by electronic absorption spectroscopy,
emission spectroscopy and viscosity measurements. The electrostatic interactions, van
der Waals interactions and/or partial intercalative binding have been observed in these
systems. The surfactant–cobalt(III) complexes were screened for their antibacterial and
antifungal activities against various microorganisms. The results were compared with
the standard drugs, Ciprofloxacin and Fluconazole respectively. Nine coordination
compounds of Cu(II) and Co(II) with Ciprofloxacin (HCp) and Enoxacin (HEx) as
ligands have been prepared and characterized. Single crystal structural determinations of
[Cu(HCp)2(ClO4)2].6H2O and [Co(HEx)2(Ex)]Cl.2CH3OH.12H2O are reported. The
crystal composed of [Cu(HCp)2(ClO4)2] units with the two perchlorate anions
semicoordinated, and uncoordinated water molecules. The copper ion, at a
crystallographic inversion centre, is in a tetragonally distorted octahedral environment
[89]. The structure of 4 consists of cationic monomeric [Co(HEx)2(Ex)]+ units, chloride
anions, and uncoordinated methanol and water molecules. The complex is sixcoordinate, with a slightly distorted octahedral environment around the metal centre.
Some complexes of ciprofloxacin and enoxacin were screened for their activity against
several bacteria, showing activity similar to that of the corresponding free ligands. All
compounds tested were more active against Gram-negative bacteria than against Grampositive bacteria. Ciprofloxacin hydrochloride and its complexes were more active than
enoxacin and its complexes. In addition, the bactericidal studies against Staphylococcus
aureus ATCC 25923 reveal that one complex exhibits the ‘‘paradoxical effect’’
(diminution in the number of bacteria killed at high drug concentration), which has been
described and related to the mechanism of action of quinolones, but three other
complexes do not, suggesting different mechanisms of bactericidal action. The ability of
Cu(HCp)2(NO3)2 . 6H2O to cleave DNA has been determined (Fig. 0-13). The results
show that the complex behaves as an efficient chemical nuclease with
ascorbate/hydrogen peroxide activation. Mechanistic studies using different inhibiting
reagents reveal that hydroxyl radicals are involved in the DNA scission process
mediated by this compound.
Fig. 0-8: Structure of Cu(HCp)2(NO3)2.6H2O
The fluoroquinolone antibiotics, ofloxacin (OF), norfloxacin (NOR), and ciprofloxacin
(CIP), can complex with Co2+ and ATP, which gives information concerning the
29
antibiotic nucleotide interaction [90]. From the fluorescence spectra and the UV
absorption spectra, we can conclude that fluoroquinolone antibiotics can not directly
complex with ATP but indirectly complex through cobalt(II), which plays an
intermediary role. The interaction of fluoroquinolone antibiotics with a nucleotide
appears to occur mainly through the phosphate group. Then we can deduce the
interaction mechanism between the fluoroquinolone antibiotics and singlestranded
DNA. This behaviour is of great importance with regard to the relevant biological role
of these drugs in the human body. Some metal [Ca(lI), Co(II), Ni(II), Cu(II), Zn(II), Al
(III) and Fe(III)] complexes of the quinolone family member (ciprofloxacin = cf) were
studied by potentiometric and spectroscopic methods in solution, The results of EPR
and polarographic methods are also included [91]. The titration curves for the metal ion-ciprofloxacin were evaluated by assuming all possible models, It was found that a lot
of protonated complexes are formed before precipitation in the systems studied, The
UV-vis results in the Cu(II)-cf system showed that in the more acidic region a 1 : 2
complex is favoured, whereas a 1 : 2 complex prevailed at higher pH values, The
coordination of the second ligand is somewhat more favoured than that of the first
ligand, and it seems probable that the 1 : 1 complex is more distorted, Some ternary
complexes [Cu(II)--cf-2,2'-bipyridyl, -glycine and -tyrosine] were studied as welL From
the A log K value, it was deduced that the formation of the mixed ligand complex in the
system Cu(II)--cf-2,2' -bipyridyl is favoured due to back-coordination. Reaction
between the quinolone antibacterial agent ciprofloxacin (abbreviation cfH) and Co(II) in
aqueous medium was studied [92]. The ability of ciprofloxacin to form metal complexes
is highly dependent on the pH value of the solution. UV spectroscopy and solubility of
ciprofloxacin. HCl were used to determine the optimal conditions for complex isolation
in the pH region between 5 and 10, where the solubility of quinolones is very low. The
isolated complex Co(cf)2.3H2O was characterized by elemental analysis, FAB-MS, TG
analysis, IR spectroscopy and magnetic measurements. Cobalt K-edge EXAFS was used
for the identification of the Co site in the complex (Fig. 0-14).
30
Fig. 0-9: Strucure of Co(cf)2.3H2O
A new quinolone–metal complex was prepared by a hydrothermal reaction in the
presence of L-histidine that served as a reducing agent for a metal [93]. The title
compound [CuII(cfH)2(CuICl2)2] is a mixed-valence Cu(II)–Cu(I) complex, which
contains two ciprofloxacin (cfH) molecules bonded to the central copper(II) atom and
two almost planar [Cu(I)Cl2] moieties. Both metal centers are connected through two
bridging atoms (chloride and quinolone oxygen). The electrochemical methods
(differential-pulse polarography and cyclovoltammetric measurements) confirmed the
presence of various copper–ciprofloxacin complex species in aqueous solution at low
concentrations used in biological activity tests and also indicated that the equilibria in
this system are very complex. The biological properties of the title compound and some
previously isolated copper–ciprofloxacin complexes ([Cu(cfH)2Cl2].6H2O and
[CuCl(cfH)(phen)]Cl.2H2O (phen = 1, 10-phenantroline) were determined and
compared (Fig. 0-15). The DNA gyrase inhibition tests and antibacterial activity tests
have shown that the effect of copper complexes is comparable to that of free quinolone,
additionally, an interesting DNA cleavage activity.
31
Fig. 0-10: Structure of [CuCl(cfH)(phen)]Cl.2H2O
A novel mixed-ligand Cu(II) complex of ciprofloxacin and phenanthroline, is
found to crystallize as a dimeric moiety containing monocationic and dicationic species
[94]. Two such dimeric moieties are found in the same unit cell leading to a dicationic
cluster. The higher negative redox potential for this cluster dampens its
antimycobacterial activity against M. smegmatis (Fig. 0-16).
Fig. 0-11: Cu(II) complex of ciprofloxacin (cfH).
32
The hydrothermal reaction of ciprofloxacin with Cu(BF4)2. 6H2O yields a copper
complex having a molecular formula, (Cu(Cf)(BF4)2).6H2O (cf= ciprofloxacin) (Fig.
0-17), which is characterized by spectroscopic and electrochemical measurements as
well as single crystal X-ray studies [a = 9,1079(13), b = 9,6112(16), c = 11,4542 (18),
Ao, α = 90,518 (19), β= 99,160 (18), γ =93:315 (19), P1bar, Z = 1] [95]. The F2O4 donor
atom set forms a (4 + 2) distorted octahedral geometry around the central copper atom;
which has a highly facile copper redox couple (0.23 V). The copper conjugate exhibits a
significant enhancement in the antitubercular activity probably arising out of its rapid
intracellular reduction leading to oxygen activation, which is detrimental to the
mycobacteria.
Fig. 0-12: Structure of (Cu(Cf)(BF4)2).6H2O
Several novel metal–quinolone compounds have been synthesized and
characterized by analytical, spectroscopic and X-ray diffraction methods. The crystal
structure of the four compounds, Na[(Cd(Cx)(Cd(Cx)(H2O)].12H2O, [Co(Cp)2(H2O)
].9H2O. [Zn(Cp)2(H2O)2].8H2O and [Cd(HCp)(Cl)].4H2O, is presented and discussed:
HCx=1-ethyl-1,4-dihydro-4-oxo(1,3)-dioxolo(4,5-g)cinnoline-3-carboxylic acid and
HCp51-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline arboxylic
33
acid [96]. In all these compounds the quinolone acts as a bidentate chelate ligand that
binds through one carboxylate oxygen atom and the exocyclic carbonyl oxygen atom.
Complexes of ciprofloxacin were screened for their activity against several bacteria,
showing activity similar to that of the ligand. In addition, the number of bacteria killed
after 3 h of incubation with the ligand, [Co(Cp)2(H2O)].9H2O.Ni(Cp)2.10H2O and
Cu(Cp)2.6H2O, was determined against S (Fig. 2-18), aureus. There is a direct
relationship between the growth rate and the lethal rate. Against growing bacteria, the
ligand is the most bactericidal and Cu(Cp)2.6H2O is the less bactericidal. On the
contrary, against non-dividing bacteria, the complexes were more bactericidal than the
ligand, with Cu(Cp)2.6H2O the most bactericidal compound.
34
Fig. 0-13: Structures of [Co(Cp) 2(H2O)].9H2O.Ni(Cp)2.10H2O and Cu(Cp)2.6H2O
The thermal behaviour of ciprofioxacin, its hydrochloride and two copper(II)
compounds of ciprofioxacin was studied by thermogravimetry (TG), differential
scanning calorimetry (DSq, evolved gas analysis (EGA) and IR spectroscopy [97]. In all
the compounds studied, profound differences in the carboxylic v(C=O) absorption were
found after heating, which can be explained by the rearrangement of the hydrogen
bonds. Reaction of the fiuoroquinolone antimicrobial ciprofioxacin with copper(II)
nitrate in the presence of 2,2'-bipyridine resulted in the isolation of the complex
[Cu(cip)(bipy)(CO0.7NO3)0.31(NO3).2H2O [98]. Reaction of an aqueous solution of
ciprofioxacin.HCI and NaCl with CuCl2 at pH 5.0 resulted in the isolation of
[Cu(cip)2]Cl2.11H2O (Fig. 2-19). The complex [Cu(cip)(bipy)(Cl)0.7(NO3)0.3]
(NO3).2H2O crystallizes in the monoclinic space group P2 1/n, with a = 13.955(8), b =
14.280(8), c= 14.192(6) A, α= 93.10(4)°, Z= 4 with R= 0.046. The selective broadening
of resonances in the 13C-NMR spectrum of ciprofioxacin by the addition of Cu2+(aq)
was employed to probe metal ion binding sites in the ligand. The protonation constants
of norfioxacin and ciprofioxacin, and the formation constants with copper(II), were
determined by potentiometric titrations at 25 oC. The additions of ciprofioxacin to metal
to form ML and ML2 complexes exhibit stepwise formation constants of logK1 6.2 and
logK2 11.1, respectively.
35
Fig. 0-14: Structure of [Cu(cip)(bipy)(Cl)0.7(NO3)0.3](NO3).2H2O
Some metal [Ca(lI), Co(II), Ni(II), Cu(II), Zn(II), Al (III) and Fe(III)] complexes of the
quinolone family member (ciprofloxacin = cf) were studied by potentiometric and
spectroscopic methods in solution, The results of EPR and polarographic methods are
also included [99]. The titration curves for the metal ion--ciprofloxacin were evaluated
by assuming all possible models, It was found that a lot of protonated complexes are
formed before precipitation in the systems studied, The UV-vis results in the Cu(II)-cf
system showed that in the more acidic region a 1 : 1 complex is favoured, whereas a 1:2
complex prevailed at higher pH values, The coordination of the second ligand is
somewhat more favoured than that of the first ligand, and it seems probable that the 1 :
1 complex is more distorted, Some ternary complexes [Cu(II)-cf-2,2'-bipyridyl, -glycine
and -tyrosine] were studied as well From the A log K value, it was deduced that the
formation of the mixed ligand complex in the system Cu(II)-cf-2,2' -bipyridyl is
favoured due to back-coordination. The synthesis of the coordination compound
[Cu(CF)Cl.6H2O is reported (Fig. 2-20). Its crystal structure is presented and discussed
[100]. The title compound crystallizes in the triclinic space group Pi with a = 9.369(2), b
= 9.57321, c = 11.206(2) A, (α = 87.37(2), β= 80.58 (2), γ = 86.25(2), V= 988.8 8, Z =
1, and Dc = 1.520 gcm-3. A structure determination, using three-dimensional MoK, x-ray
data, resulted in conventional R and Rw values of 0.0399 and 0.0988, respectively, for
3495 unique reflexions for which I > 2 a(I). Refinement was based on F2. The copper
atom at the center of inversion is surrounded in a plane by four oxygens (two of the
carboxylate grouts, two of the carbonyl groups), the corresponding Cu-O distances are
1.928(2) and 1.931(2) A, respectively. The two chlorine atoms are axially coordinated
to Cu at larger distances than 2.688(2) A. The Cl atoms appeared to be disordered over
three positions. The nearly planar moieties of Cu(CF), are packed parallel in the unit
cell interconnected via hydrogen bonds of the type N-H.. .O, O-H.. . Cl and O-H….O.
The results of other physical measurements (TG, FT-IR, and various analyses) are also
included.
36
Fig. 0-15: Structure of [Cu(CF)Cl.6H2O complex.
Ciprofloxacinium(1+) ciprofloxacinium(2+) tetrachlorocuprate(II) chloride hydrate,
(cfH2)(cfH3)[CuCl]Cl.H2O, isolated and its structure was determined by X-ray
crystallography [101]. This is a typical ionic compound with no direct bonds between
the quinolone and metal. Both ciprofloxacin (cfH = 1-cyclopropyl-6-fluoro-1,4-dihydro4-oxo-7-(1-piperazinyl)-3-quinoline arboxylic acid) molecules are nonequivalent and
are protonated thus being unable to coordinate to the copper. The new complex has been
characterised by intrinsic fluorescence emission and UV spectroscopy. The title
compound as well as two previously isolated copper complexes,
[Cu(cfH)(H2O)3]SO4.2HO, and [Cu(cfH)2]Cl26HO, (Fig. 2-21) were tested against the
growth of various Gram positive and Gram negative microorganisms. Antimicrobial
activities were evaluated using the agar diffusion test. Since ciprofloxacin alone has the
ability to bind to DNA, the binding of a new compound has also been tested by UV
.
spectroscopy. Our results reveal that (cfH2)(cfH3)[CuCl]Cl H2O slightly thermally
destabilise the linear double stranded DNA at pH 7.
37
Fig. 0-16: Sructure of (cfH2)(cfH3)[CuCl]Cl.H2
A neutral dimeric copper conjugate of sparfloxacin (Fig. 2-22) and its phenanthroline
adduct show considerable enhancement in their antiproliferative activities against
hormone independent BT20 breast cancer cells [102].
38
Fig. 0-17: Sparfloxacin CuII Complexes.
Two iron(III) complexes of Ciprofloxacin were synthesized by reaction of the
ligand with iron(III) chloride hexahydrate in different solutions [103]. The nature of
bonding of the ligands and the structure of the isolated metal complexes were elucidated
on the basis of their physical and spectroscopic studies (Fig. 2-23). The infrared spectra
suggest that two classes of compounds were obtained: molecular complex in which the
ligands were bidentately bonded to the metal through the ring carbonyl oxygen and one
of the oxygen of the carboxylate group and the ionic complex consisting of a
tetrachlorometalate ion which is electrostatically attached to the ligand. The
antibacterial activities of the products against various microorganisms were tested and it
was established that their activities were comparable with those of their parent drug.
Toxicological studies were carried out in which therapeutic doses of the Ciprofloxacin
drug and the metal complexes were administered to albino rats and the results showed
that the metal complexes are not toxic.
39
Fig. 0-18: Iron(III) complexes of Ciprofloxacin.
A vanadium complex [104] was prepared from a water solution of VOSO4 and
cfH. The crystals were very unstable and contained a high amount of disordered water
molecules, so the exact solution of the structure has not yet been possible. The tentative
formula of the complex is [VO(cfH)2]SO4.10H2O with a typical chelate bonding of
metal to 4-oxo and carboxylic oxygens of quinolone. The iron(III) complex with cfH
and nitriloacetate (nta) as ligands, [Fe(cfH)(nta)].3.5H2O was isolated from water
solutions of cfH.HCl, Fe(NO3)3 and nitrilo- triacetate (nta) (disodium salt) [105]. Dilute
ammonia solution was used to adjust the pH to 7. The structure consists of a neutral
[Fe(cfH)(nta)] complex and 3.5 water molecules. The iron is coordinated to the keto
(Fe(1)-O(1)=1.942(8) A°) and the carboxylic oxygen (Fe(1)-O(2)=1.91(1) A°) of the
cfH ligand to form a six-membered ring. The remaining four coordination sites are
occupied by an nta ligand (Fe(1)-O(4)=2.037(9) A°, Fe(1)-O(6)=1.969(9) A°, Fe(1)O(8)=1.983(9) A°, Fe(1)-N(4)=2.21(1) A°). The piperazinyl ring of the cfH ligand is
protonated on the external nitrogen (Fig. 2-24).
40
Fig. 0-19: Iron(III) complex with Ciprofloxacin.
Two copper(II) complexes were prepared with cfH, two with cxH and one with
ofloxacin. Additionally, five mixed ligand complexes were also isolated. Both coppercfH complexes were prepared from water solutions of cfH and copper(II) salts (chloride,
sulphate). In the complex [Cu(cfH)2Cl2].6H2O the copper atom is positioned at the
center of inversion and surrounded by four oxygen atoms, Cu(1)-O(1)=1.928(2) A° and
Cu(1)-O(2)=1.931(2) A° [106]. The two chloride ions are axially coordinated to copper
at longer distances (2.688(2) A°) and appear to be disordered over three positions. In the
second complex of copper and cfH [Cu(cfH)(H2O)3]SO4.2H2O [107] (Fig. 2-25), only
one molecule of quinolone is coordinated to the metal. The coordination environment
around the central copper(II) ion in the structure is a slightly distorted square pyramid.
Ciprofloxacin is bonded to the metal through a carbonyl atom (Cu-O(3)=1.939(1) A°)
and a carboxylic atom (Cu-O(1)=1.915(2) A°). Two watermolecules are coordinated to
copper in the basal plane (Cu-O(8)=1.972(2) A°) and (Cu-O(9)=1.989(2) A°).The apical
water molecule is coordinated at a longer distance (Cu-O(10)=2.174(2) A°).
Fig. 0-20: Copper(II) complexes with Ciprofloxacin.
41
The
crystal
structure
of
cerium(III)
complex
of
cfH
[Ce(cf)2(H2O)4]Cl(H2O)3.25(C2H5OH)0.25 was published [108]. The quinolone is again
coordinated through 3-carboxyl and 4-keto oxygens and the coordination number of
cerium is eight. In the magnesium adduct of cfH (cfH2)2[Mg(H2O)6](SO4)2.6H2O [109],
magnesium is not bonded to the quinolone molecule. The quinolone is protonated at the
terminal nitrogen atom of piperazine residue. The hydrogen atom of the carboxylic
group is hydrogen bonded to the carbonyl oxygen atom, thus preventing the bonding of
the metal to this part of the molecule. The magnesium ion is coordinated by six water
molecules forming a [Mg(H2O)6]2 cation with a nearly regular octahedral geometry.
This is the only example of a metal/quinolone ionic compound reported with the water
molecules coordinated to the metal (Fig. 2-26).
Fig. 0-21: Structure of (cfH2)2[Mg(H2O)6](SO4)2.6H2O
Two bismuth(III) compounds of cfH have been prepared (cfH3)(cfH2)[BiCl6].2H2O and
(cfH3)2[Bi2Cl10].4H2O [110]. In the former, one of the cfH molecules is protonated at
carbonyl oxygen and the terminal nitrogen of the piperazine residue, whereas the other
is protonated only at the latter nitrogen atom (Fig. 2-27). The charge of the isolated
hexachlorobismuthate(III) anions is compensated by protonated cfH molecules. Due to
their high charge, [BiCl6]3- anions are not very common as the formation of polynuclear
anions seems to be preferred [111-113]. In the latter compound Bi(III) ions are
coordinated by chloride ions forming dinuclear [Bi2Cl10]4- anions. Both quinolone
molecules are doubly protonated in this compound.
Fig. 0-22: Structure of (cfH3)(cfH2)[BiCl6].2H2O
42
The zinc compound (nfH3)(nfH2)[ZnCl4]Cl.H2O is isotypic to the copper/norfloxacin
compound (see above). The zinc compound of cfH with the formula (cfH3)[ZnCl4].H2O
[114] is also very similar to the zinc compound of norfloxacin. There are distinctive
layers of quinolone molecules in the structure which are crosslinked through extensive
hydrogen bonding. The complexation of fluoroquinolone antimicrobials with various
metal ions have been studied in aqueous solution (pD 2.5, 37°C) by 1H and 13C-NMR
spectroscopy [115]. The compounds examined are levofloxacin, ciprofloxacin and
lomefloxacin. In each drug, new signals have appeared by the addition of Al3+,
suggesting that the complexes are formed between the drug and Al3+ and that the ligand
exchange is slow on the NMR time scale. Solution structure of the major species in the
presence of 2.0 mol equiv of Al3+ has been proposed based on the large downfield shifts
of some specific protons. Signals of both the coordinated and free drugs have shown
slight broadening at 90°C due to the enhanced rate in ligand dissociation process,
though the coalescence phenomena are not observed even at this temperature. Thus, the
complexes are supposed to be stable at the physiological condition. Titration
experiments have revealed that the binding ability of levofloxacin toward Al3+ is much
stronger than that of ciprofloxacin and lomefloxacin at pD 2.5. In contrast to the
complexation with Al3+, the binding of these drugs with other metal ions such as Ca2+
and Mg2+ is much weaker; NMR signals have shown no appreciable downfield shift by
the addition of Ca2+ and Mg2+. Based on these results, it is concluded that the
fluoroquinolone antimicrobials examined in the present study at pD 2.5 exist as stable
complexes in the presence of Al3+ and the absorptivity of the drugs on oral
administration could be affected by Al3+.
Quinolones can bind several divalent metal ions, including Mg2+, Ca2+, Mn2+,
Fe2+/3+, Co2+, Ni2+, Cu2+, Zn2+, Cd2+, and Al3+ [106] and may result in change in their
activity. Mg2+ and Al3+ were found to decrease the activity of the drugs whereas Fe3+
and Zn2+ complexes were found to exhibit higher activities. The crystal structures of the
Ni2+ and Cu2+ complexes of cinoxacin and ciprofloxacin have been solved, in which the
metals are found to bind to the a-carboxylketo moiety to form 1:2 metal-to-drug
complexes. The complexes have a pseudo-axial symmetry with the two drug ligands
bound symmetrically at the equatorial positions. The drug was also determined by
means of crystallography to form a 1:3 Co2+ :drug3 complex. A few metal complexes
(Fe3+, Cu2+, and Bi3+) of quinolones were prepared in acidic solutions, from which
crystals were obtained and structures solved. However, the metal ions in these crystals
do not bind directly to the drugs owing to protonation of the carboxylate group, which
may not be relevant to the drug action under physiological conditions. The formation of
M2+ (quinolone) (2,2́dipyridine) ternary complexes (M = Co(II), Ni(II), and Cu(II)) was
observed by means of electrospray ionization and laser desorption mass spectroscopy. A
recent theoretical study suggested that metal binding to these drugs is associated with
the action of these drugs, and fluorescence quenching measurements indicate the
presence of a stacking which has been suggested to be associated with the DNA
intercalation capacities of the drugs and their Cu2+ complexes.
43
REFERENCES
1- Ball P (2000). "Quinolone generations: natural history or natural selection?". J.
Antimicrob. Chemother. 46 Suppl T1 (Supplement 3): 17–24. PMID 10997595.
http://jac.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=10997595.
2- "New Classification and Update on the Quinolone Antibiotics - May 1, 2000 American Academy of Family Physicians". http://www.aafp.org/afp/20000501/
2741.html. Retrieved 2008-03-18.
3- Nalidixic Acid, case number 389-08-02, listing mechanism AB, NTP (1989)b.
4- Oliphant CM, Green GM (February 2002). "Quinolones: a comprehensive review".
Am Fam Physician 65 (3): 455–64. PMID 11858629. http://www.aafp.org/afp/
20020201/455.html.
5- Paul G. Ambrose; Robert C. Owens, Jr (1 March 2000). "Clinical Usefulness Of
Quinolones". Seminars in Respiratory and Critical Care Medicine (Medscape).
http://www.medscape.com/viewarticle/410872_6.
6- The European Medicines Agency (24 July 2008). "EMEA Restricts Use of Oral
Norfloxacin Drugs in UTIs". Doctor's Guide. http://www.docguide.com/news/
content.nsf/news/852571020057CCF68525749000687709.
7- Schmid, Randolph E. (May 1, 2006). "Drug Company Taking Tequin Off Market".
Associated Press. http://www.sfgate.com/cgi-bin/article.cgi?file=/news/archive/
2006/05/01/national/w120748D88.DTL&type=health. Retrieved 2006-05-01.
8- Fiscella RG, Lewis CC, Jensen MK (October 2007). "Topical ophthalmic fourthgeneration fluoroquinolones: Appropriate use and cost considerations". Am J Health
Syst Pharm 64 (19): 2069–73. doi:10.2146/ajhp060667. PMID 17893419.
http://www.ajhp.org/cgi/pmidlookup?view=long&pmid=17893419.
9- The European Medicines Agency (EMEA); Danish Medicines Agency (24 July
2008). "EMEA recommends restricting the use of oral moxifloxacin-containing
medicines".
10- Miravitlles M, Anzueto A (July 2008). "Moxifloxacin: a respiratory
fluoroquinolone".
Expert
Opin
Pharmacother
9
(10):
1755–72.
doi:10.1517/14656566.9.10.1755. PMID 18570608.
11- UN (2005). "Consolidated list of products - Pharmaceuticals 12th issue" (PDF).
United Nations. http://www.un.org/esa/coordination/CL12.pdf.
12- Paul G. Ambrose; Robert C. Owens, Jr (1 March 2000). "New Antibiotics in
Pulmonary and Critical Care Medicine: Classification Of Quinolones By
Generation". USA: Medscape. http://www.medscape.com/viewarticle/410872_4.
13- sanofi-aventis U.S. LLC (September 2008). "NegGram® Caplets (nalidixic acid,
USP)" (PDF). USA: FDA. http://www.accessdata.fda.gov/drugsatfda_docs/label
/2009/014214s058lbl.pdf.
14- Wentland MP: In memoriam: George Y. Lesher, Ph.D., in Hooper DC, Wolfson JS
(eds): Quinolone antimicrobial agents, ed 2., Washington DC, American Society for
Microbiology : XIII - XIV, 1993.
44
15- Hooper, DC. (Mar-Apr 2001). "Emerging mechanisms of fluoroquinolone
resistance." (PDF). Emerg Infect Dis 7 (2): 337–41. doi:10.3201/eid0702.010239.
PMID 11294736. PMC 2631735. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC
2631735/pdf/11294736.pdf.
16- Elsea, SH.; Osheroff, N.; Nitiss, JL. (July 1992). "Cytotoxicity of quinolones toward
the quinolone CP-115,953 in yeast." (pdf). J Biol Chem 267 (19): 13150–3.
PMID 1320012. http://www.jbc.org/content/267/19/13150.full.pdf.
17- Muto, CA.; Jernigan, JA.; Ostrowsky, BE.; Richet, HM.; Jarvis, WR.; Boyce, JM.;
Farr, BM. (May 2003). "SHEA guideline for preventing nosocomial transmission of
multidrug-resistant strains of Staphylococcus aureus and enterococcus.". Infect
Control Hosp Epidemiol 24 (5): 362–86. doi:10.1086/502213. PMID 12785411.
18- Dr Ralf-Peter Vonberg. "Clostridium difficile: a challenge for hospitals". European
Center for Disease Prevention and Control. Institute for Medical Microbiology and
Hospital Epidemiology: IHE. http://www.ihe-online.com/feature-articles/clostridium
-difficile-a-challenge-for-hospitals/trackback/1/index.html. Retrieved 27 July 2009.
19- Tacconelli, E.; De Angelis, G.; Cataldo, MA.; Pozzi, E.; Cauda, R. (January 2008).
"Does antibiotic exposure increase the risk of methicillin-resistant Staphylococcus
aureus (MRSA) isolation? A systematic review and meta-analysis.". J Antimicrob
Chemother 61 (1): 26–38. doi:10.1093/jac/dkm416. PMID 17986491. http://jac.
oxfordjournals.org/cgi/content/full/61/1/26.
20- Liu, H.; Mulholland, SG. (July 2005). "Appropriate antibiotic treatment of
genitourinary infections in hospitalized patients.". Am J Med 118 Suppl 7A: 14S–
20S. doi:10.1016/j.amjmed.2005.05.009. PMID 15993673.
21- B.P. Kamat, J. Seetharamappa, J. Pharm. Biomed. Anal. 35 (2004) 655–664.
22- N. Seedher, Indian J. Pharm. Sci. 62 (2000) 16–20.
23- F.L. Cui, J. Fan, J.P. Li, Z.De. Hu, Bioorg. Med. Chem. 12 (2004) 151–157.
24- B.C. Channu, H.N. Kalpana, G.B. Eregowda, C. Dass, P.J. Houghton, K.N.
Thimmaiah, J. Pharm. Biomed. Anal. 21 (1999) 775–785.
25- Wein, Alan J.; Kavoussi, Louis R.; Novick, Andrew C.; Partin, Alan W.; Peters,
Craig A. (19 March 2007). Campbell-Walsh Urology Review Manual (Ninth ed.).
Saunders. ISBN 978-1416031550. http://books.google.com/id=KGVqAAAAMAAJ.
26- Hing-Biu Lee, Thomas E. Peart, M. Lewina Svoboda, Journal of Chromatography
A, 1139 (2007) 45–52
27- Eleni A. Christodoulou, Victoria F. Samanidou , Ioannis N. Papadoyannis, Journal
of Chromatography B, 859 (2007) 246–255.
28- R.A. Robson, International Journal of Antimicrobial Agents 2 (1992)3-10.
29- Guo-Hui Wan a, Hua Cui, Yi-Lan Pan, Ping Zheng, Li-Juan Liu, Journal of
Chromatography B, 843 (2006) 1–9.
30- Schaumann, R.; Rodloff, A. C. (January 2007). "Activities of Quinolones Against
Obligately Anaerobic Bacteria" (PDF). Anti-Infective Agents in Medicinal
Chemistry (Formerly Current Medicinal Chemistry - Anti-Infective Agents)
(Bentham Science Publishers) 6 (1): 49–56. http://www.bentham.org/cmcaia/sample
/cmcaia%206-1/0004Y.pdf.
45
31- Chang Y.H.; Se H.K.; Young K.K (22 July 1997). "Novel 5-amino-6methylquinolone antibacterials: A new class of non-6-fluoroquinolones". Bioorganic
& Medicinal Chemistry Letters (Elsevier) 7 (14): 1875–1878. doi:10.1016/S0960894X(97)00324-7.
32- CANN HM, VERHULST HL (January 1961). "Fatal acute chloroquine poisoning in
children". Pediatrics 27 (1): 95–102. PMID 13690445. http://pediatrics.aappub
lications.org/cgi/content/abstract/27/1/95.
33- Murray, Robert K.; Granner, Darryl K.; Mayes, Peter A.; Rodwell, Victor W. (1
July 2006). "Protein Synthesis and the Genetic Code". Harper's Illustrated
Biochemistry (27 ed.). McGraw-Hill Medical. p. 378. ISBN 0071461973.
http://books.google.com/?id=QrJCZ1v5T6AC. "The most useful members of this
class of antibiotics (eg tetracyclines, lincomycin, erythromycin and
chloramphenicol) do not interact with components of eukaryotic ribosomal particles
and thus are not toxic to eukaryotes..."
34- Bergan T.; Bayer (1988). "Pharmacokinetics of fluorinated quinolones". Academic
Press: 119–154.
35- Bergan T; Dalhoff A, Thorsteinsson SB (1985). A review of the pharmacokinetics
and tissue penetration of ciprofloxacin. pp. 23–36.
36- Castora, FJ.; Vissering, FF.; Simpson, MV. (September 1983). "The effect of
bacterial DNA gyrase inhibitors on DNA synthesis in mammalian mitochondria.".
Biochim Biophys Acta 740 (4): 417–27. PMID 6309236.
37- Kaplowitz, Neil (2005). "Hepatology highlights". Hepatology 41: 227.
doi:10.1002/hep.20596.
38- Enzmann, H.; Wiemann, C.; Ahr, HJ.; Schlüter, G. (April 1999). "Damage to
mitochondrial DNA induced by the quinolone Bay y 3118 in embryonic turkey
liver.". Mutat Res 425 (2): 213–24. PMID 10216214.
39- MCQUEEN CA.; WILLIAMS GM. (1987). "Effects of quinolone antibiotics in tests
for genotoxicity". Am. J. Med 82 (Suppl. 4A): 94–96.
40- Holden, HE.; Barett, JF.; Huntington, CM.; Muehlbauer, PA.; Wahrenburg, MG.
(1989). "Genetic profile of a nalidixic acid analog: a model for the mechanism of
sister chromatid exchange induction.". Environ Mol Mutagen 13 (3): 238–52.
doi:10.1002/em.2850130308. PMID 2539998.
41- Suto, MJ.; Domagala, JM.; Roland, GE.; Mailloux, GB.; Cohen, MA. (December
1992). "Fluoroquinolones: relationships between structural variations, mammalian
cell cytotoxicity, and antimicrobial activity.". J Med Chem 35 (25): 4745–50.
doi:10.1021/jm00103a013. PMID 1469702.
42- Nelson, JM.; Chiller, TM.; Powers, JH.; Angulo, FJ. (Apr 2007). "Fluoroquinoloneresistant Campylobacter species and the withdrawal of fluoroquinolones from use in
poultry: a public health success story.". Clin Infect Dis 44 (7): 977–80.
doi:10.1086/512369. PMID 17342653.
43- Padeĭskaia, EN. (2003). "[Norfloxacin: more than 20 years of clinical use, the results
and place among fluoroquinolones in modern chemotherapy for infections]".
Antibiot Khimioter 48 (9): 28–36. PMID 15002177.
44- Rafalsky, V.; Andreeva, I.; Rjabkova, E.; Rafalsky, Vladimir V (2006). "Quinolones
for uncomplicated acute cystitis in women.". Cochrane Database Syst Rev 3:
CD003597. doi:10.1002/14651858.CD003597.pub2. PMID 16856014.
46
45- "HQ 545710". faqs.org. 30 October 1998. http://www.faqs.org/rulings/rulings
1999HQ545710.html.
46- Merck Sharp & Dohme (September 2008). "TABLETS NOROXIN
(NORFLOXACIN)" (PDF). USA: FDA. http://www.accessdata.fda.gov/drugsatfda
_docs/label/2008/019384s052lbl.pdf.
47- "EMEA Restricts Use of Oral Norfloxacin Drugs in UTIs". UK: DGNews. 24 July
2008. http://www.docguide.com/news/content.nsf/news/852571020057CCF685257
49000687709
48- Merck Sharp & Dohme (September 2000). "Chibroxin (Norfloxacin) Ophthalmic
solution" (PDF). USA: FDA. http://www.accessdata.fda.gov/drugsatfda_docs/label
/2001/19757S10lbl.pdf.
49- "Showing drug card for Norfloxacin (DB01059)". Canada: DrugBank.ca. 19
February. http://www.drugbank.ca/drugs/DB01059.
50- A.R. Martin, in: J.N. Delgado, W.A. Remers (Eds.), Textbook of Organic Medicinal
and Pharmaceutical Chemistry, Lippincott, Philadelphia, PA, 1991, p. 155.
51- Antonio Rosato, Cesare Vitali, Nicolino De Laurentisa, Domenico Armenise, Maria
Antonietta Milillo, Phytomedicine 14 (2007) 727–732.
52- Drlica K, Zhao X (1 September 1997). "DNA gyrase, topoisomerase IV, and the 4quinolones". Microbiol Mol Biol Rev. 61 (3): 377–92. PMID 9293187.
PMC 232616. http://mmbr.asm.org/cgi/pmidlookup?view=long&pmid=9293187.
53- Robinson MJ, Martin BA, Gootz TD, McGuirk PR, Osheroff N (April 1992).
"Effects of novel fluoroquinolones on the catalytic activities of eukaryotic
topoisomerase II: Influence of the C-8 fluorine group" (PDF). Antimicrob. Agents
Chemother. 36 (4): 751–6. PMID 1323952. PMC 189387.http://aac.asm.org/
cgi/reprint/36/4/751.pdf.
54- Sissi C, Palumbo M (November 2003). "The quinolone family: from antibacterial to
anticancer agents". Curr Med Chem Anticancer Agents 3 (6): 439–50.
doi:10.2174/1568011033482279. PMID 14529452.
55- Hussy P, Maass G, Tümmler B, Grosse F, Schomburg U (June 1986). "Effect of 4quinolones and novobiocin on calf thymus DNA polymerase alpha primase
complex, topoisomerases I and II, and growth of mammalian lymphoblasts".
Antimicrob. Agents Chemother. 29 (6): 1073–8. PMID 3015015. PMC 180502.
http://aac.asm.org/cgi/reprint/29/6/1073.pdf.
56- Hosomi JA, Maeda Y, Oomori T, Irikura and T. Yokota (1988). "Mutagenicity of
norfloxacin and AM-833 in bacteria and mammalian cells". Rev. Infect. Dis 10
(Suppl. 1): S148–9.
57- Elsea SH, Osheroff N, Nitiss JL (July 1992). "Cytotoxicity of quinolones toward
the quinolone CP-115,953 in yeast". J. Biol. Chem. 267 (19): 13150–3.
PMID 1320012. http://www.jbc.org/cgi/reprint/267/19/13150.
58- Yaseen A. Al-Soud; Najim A. Al-Masoudi (2003). "A new class of
dihaloquinolones bearing N'-aldehydoglycosylhydrazides, mercapto-1,2,4-triazole,
oxadiazoline and a-amino ester precursors: synthesis and antimicrobial activity". J.
Braz. Chem. Soc 14 (5). doi:10.1590/S0103-50532003000500014.
59- Angel A.J. Torriero, Eloy Salinas , Julio Raba, Juana J. Silber, Biosensors and
Bioelectronics 22 (2006) 109–115.
60- Cooper JG, Harboe K, Frost SK, Skadberg Ø, JG (April 2005). "Ciprofloxacin
interacts with thyroid replacement therapy". BMJ 330 (7498): 1002.
doi:10.1136/bmj.330.7498.1002. ISSN 0959-8138. PMID 15860826.
47
61- Drlica K, Zhao X, K (September 1, 1997). "DNA gyrase, topoisomerase IV, and the
4-quinolones". Microbiol Mol Biol Rev. 61 (3): 377–92. ISSN 1092-2172.
PMID 9293187.
62- Robinson MJ, Martin BA, Gootz TD, McGuirk PR, Osheroff N, MJ (April 1992).
"Effects of novel fluoroquinolones on the catalytic activities of eukaryotic
topoisomerase II: Influence of the C-8 fluorine group" (PDF). Antimicrob. Agents
Chemother. 36 (4): 751–6. ISSN 0066-4804. PMID 1323952. PMC 189387.
http://aac.asm.org/cgi/reprint/36/4/751.pdf.
63- Sissi C, Palumbo M, C (November 2003). "The quinolone family: from antibacterial
to anticancer agents". Curr Med Chem Anticancer Agents 3 (6): 439–50.
doi:10.2174/1568011033482279. ISSN 1568-0118.
64- Hussy P, Maass G, Tümmler B, Grosse F, Schomburg U, P (June 1986). "Effect of
4-quinolones and novobiocin on calf thymus DNA polymerase alpha primase
complex, topoisomerases I and II, and growth of mammalian lymphoblasts" (PDF).
Antimicrob. Agents Chemother. 29 (6): 1073–8. ISSN 0066-4804. PMID 3015015.
PMC 180502. http://aac.asm.org/cgi/reprint/29/6/1073.pdf.
65- Lawrence JW, Darkin-Rattray S, Xie F, Neims AH, Rowe TC, JW (February 1993).
"4-Quinolones cause a selective loss of mitochondrial DNA from mouse L1210
leukemia cells" (Free full text). J. Cell. Biochem. 51 (2): 165–74.
doi:10.1002/jcb.240510208. ISSN 0730-2312. PMID 8440750.
66- Kashida Y, Sasaki YF, Ohsawa K, Y (October 2002). "Mechanistic study on
flumequine hepatocarcinogenicity focusing on DNA damage in mice". Toxicol. Sci.
69 (2): 317–21. doi:10.1093/toxsci/69.2.317. ISSN 1096-6080. PMID 12377980.
67- Fabiana L. Alovero, Marıá E. Oliver, Ruben H. Manzo, International Journal of
Antimicrobial Agents 21 (2003) 446-451.
68- Xiangdong Wei and Li-June Ming, Inorg. Chem. 1998, 37, 2255-2262.
69- Jamil Al-Mustafa, Acta Chim. Slov. 2002, 49, 457−466.
70- Eleni K. Efthimiadou, George Psomas, Yiannis Sanakis, Nikos Katsaros and
Alexandra Karaliota, Journal of Inorganic Biochemistry 101 (2007) 525–535.
71- Moamen S. Refat, Spectrochimica Acta Part A 68 (2007) 1393–1405.
72- Anwar R. Shaikh, Rajani Giridhar, Mange Ram Yadav, International Journal of
Pharmaceutics 332 (2007) 24–30.
73- G.P. Voga, J.C. Belchior, Thermochimica Acta 452 (2007) 140–148.
74- Weiwei Bian, Chongqiu Jiang, Clinica Chimica Acta 368 (2006) 144 – 148.
75- Sadeek A. Sadeek, Journal of Molecular Structure 753 (2005) 1–12.
76- Michael E. El-Kommos, Gamal A. Saleh, Samia M. El-Gizawi, Mohamed A. AbouElwafa, Talanta 60 (2003) 1033_/1050.
77- Teraboon Pojanagaroon , Surasak Watanesk , Vichitr Rattanaphani , Saisunee
Liawrungrath, Talanta 58 (2002) 1293_/1300.
78- Fei Gao, Pin Yang, Jun Xie, and Hongfei Wang,Journal of Inorganic Biochemistry,
60, 61-67 (1995).
79- Predrag T. Djurdjevic, Milena Jelikic-Stankov , Dejan Stankov, Analytica Chimica
Acta 300 (1995) 253-259.
80- DONG-SUN LEE, HEE-JUNG HAN, KUN KIM, WON-BONG PARK, JUNG-KIL
CHO and JAE-HYUN KIM, journal of Pharmaceutical & Biomedical Analysis.
Vol. 12. No.2. pp. 157-IM. 1994.
81- H.N. Alkaysi a, M.H. Abdel-Hay , M. Sheikh Salem , A.M. Gharaibeh and T.E.
Na'was, International Journal of Pharmaceutics, 87 (1992) 73-77.
82- Huichun Zhang 1, Ching-Hua Huang, Chemosphere 66 (2007) 1502–1512.
48
83- Z.F. Chen, R.G. Xiong, J.L. Zuo, Z. Guo, X.Z. You, H.K. Fun, J. Chem. Soc. Dalton
Trans. (2000) 4013.
84- Z.F. Chen, B.Q. Li, Y.R. Xie, R.G. Xiong, X.Z. You, X.L. Feng, Inorg. Chem.
Commun. 4 (2001) 346.
85- Z.F. Chen, R.G. Xiong, J. Zhang, X.T. Chen, Z.L. Xue, X.Z. You, Inorg. Chem. 40
(2001) 4075.
86- I. Turel, K. Gruber, I. Leban, N. Bukovec, J. Inorg. Biochem. 61 (1996) 197.
87- M. Zupancˇicˇ, I. Turel, P. Bukovec, A.J.P. White, D.J. Williams, Croat. Chem.
Acta 74 (2001) 61.
88- R. Senthil Kumar, S. Arunachalam, Biophysical Chemistry 136 (2008) 136–144.
89- N. Jimeńez-Garrido a, L. Perello´, R. Ortiz a, G. Alzuet , M. Gonza´lez-A´ lvarez
,E. Cantoń , M. Liu-Gonza´lez , S. Garcıá-Granda , M. Pe´rez-Priede , Journal of
Inorganic Biochemistry 99 (2005) 677–689.
90- Shuqing Wu , Wujuan Zhang , Xingguo Chen , Zhide Hu , Martin Hooper , Beveley
Hooper , Zhengfeng Zhao, Spectrochimica Acta Part A 57 (2001) 1317–1323.
91- IZTOK TUREL and NATASA BUKOVEC, Polyhedron Vol. 15, No.2, pp. 269
275, 1996
92- Marija Zupancic, Iztok Arcon Peter Bukovec, and Alojz Kodre , CCACAA 75 (1) 112 (2002).
93- Petra Drevensek , Tatjana Zupancic, Boris Pihlar, Roman Jerala , Uwe Kolitsch
,Andreja Plaper , Iztok Turel, Journal of Inorganic Biochemistry 99 (2005) 432–442.
94- Dilip Kumar Saha,a Uday Sandbhor, K. Shirisha,a Subhash Padhye, Dileep
Deobagkar, Christopher E. Ansond and Annie K. Powell, Bioorganic & Medicinal
Chemistry Letters 14 (2004) 3027–3032.
95- Dilip Kumar Saha , Subhash Padhye, Christopher E. Anson, Annie K. Powell,
Inorganic Chemistry Communications 5 (2002) 1022–1027.
96- M.P. Lopez-Gresa, R. Ortiz, L. Perello, J. Latorre, M. Liu-Gonzalez,S. GarcıaGranda, M. Perez-Priede , E. Canton, Journal of Inorganic Biochemistry 92 (2002)
65–74.
97- Iztok Turel, Peter Bukovec, Thermochimica Acta 287 (1996) 311-318.
98- Steven c. Wallis, Lawrence R. Gahan, Bruce G. Charles, Trevor W. Hambley, and
Paul A. Duckworth, Journal of Inorganic Biochemistry, 62, 1-16 (1996).
99- ETELKA FARKAS, Polyhedron Vol. 15, No.2, pp. 269 275, 1996.
100- Iztok Turel, Ivan Leban, and Natah Bukovec, Journal of Inorganic biochemistry,
56,273-282 (1994).
101- Petra Drevenšek, Amalija Golobič, Iztok Turel, Acta Chim. Slov. 2002, 49,
857−870.
102- Dipti Shingnapurkar , Ray Butcher , Zahra Afrasiabi, Ekkhard Sinn , Fakhara
Ahmed , Fazlul Sarkar , Subhash Padhye, Inorganic Chemistry Communications 10
(2007) 459–462.
103- J. A. Obaleye, C. A. Akinremi, E. A. Balogun and J. O. Adebayo, African
Journal of Biotechnology Vol. 6 (24), pp. 2826-2832.
104- D. Rehder, J. Costa Pessoa, C.F.G.C. Geraldes, T. Kabanos, T. Kiss, B. Meier,
G. Micera, L. Pettersson, M. Rangel, A. Salifoglou, I. Turel, D. Wang, J. Biol.
Inorg. Chem., in press.
105- S.C. Wallis, L.R. Gahan, B.G. Charles, T.W. Hambley, Polyhedron 14 (1995)
2835.
106- I. Turel, I. Leban, N. Bukovec, J. Inorg. Biochem. 56 (1994) 273.
107- I. Turel, L. Golicˇ, O.L. Ruiz Ramirez, Acta Chim. Slov. 46 (1999) 203.
108- J.B. Li, P. Yang, F. Gao, G.Y. Han, K.B. Yu, Chinese J. Chem.19 (2001) 598.
49
109- I. Turel, I. Leban, M. Zupancˇicˇ, P. Bukovec, K. Gruber, Acta Crystallogr.,
Sect. C 52 (1996) 2443.
110- I. Turel, L. Golicˇ, P. Bukovec, M. Gubina, J. Inorg. Biochem. 71 (1998) 53.
111- F. Lazarini, Acta Crystallogr., Sect. C 43 (1987) 637.
112- B. Blazˇicˇ, F. Lazarini, Acta Crystallogr., Sect. C 41 (1985) 1619.
113- F. Lazarini, Acta Crystallogr., Sect. C 43 (1987) 875.
114- M. Zupancˇicˇ, I. Turel, P. Bukovec, A.J.P. White, D.J. Williams, Croat. Chem.
Acta 74 (2001) 61.
115- Masahiro Sakai, Akihiro Hara, Saeko Anjo , Mikio Nakamura, Journal of
Pharmaceutical and Biomedical Analysis 18 (1999) 1057–1067.
50
CHAPTER 3
3-1- Analgesics Drugs
An analgesic (also known as a painkiller) is any member of the group of drugs
used to relieve pain (achieve analgesia).
). The word analgesic derives from Greek anan
("without") and algos ("pain"). Analgesic drugs act in various ways on the peripheral
and central nervous systems; they include paracetamol (para-acetylaminophenol,
acetylaminophenol, also
known in the US as acetaminophen), the non-steroidal anti-inflammatory
inflammatory drugs
(NSAIDs) such as the salicylates,
salicylates narcotic drugs such as morphine,, synthetic drugs with
narcotic properties such as tramadol. In choosing analgesics, the severity and response
respon
to other medication determines the choice of agent; the WHO pain ladder,
ladder originally
developed in cancer-related
related pain, is
is widely applied to find suitable drugs in a stepwise
manner [1].. The analgesic choice is also determined by the type of pain: for neuropathic
pain,, traditional analgesics are less effective, and there is often benefit from classes of
drugs that are not normally considered analgesics, such as tricyclic antidepressants and
anticonvulsants [2].
Fig. 3-1: Structure of ibuprofen.
ibuprofen
Ibuprofen (pronounced from the now outdated nomenclature iso-butyliso
propanoic-phenolic
phenolic acid) is a non-steroidal anti-inflammatory drug (NSAID) originally
marketed as Brufen, and since then under various other trademarks (see tradenames
section), most notably Nurofen,
Nurofen Advil and Motrin. It is used for relief of symptoms of
arthritis, primary dysmenorrhea,
dysmenorrhea fever, and as an analgesic,, especially where there is an
inflammatory component. Ibuprofen is known to have an antiplatelet effect, though it is
relatively mild and short-lived
short
when compared with that of aspirin or other betterknown antiplatelet drugs. Ibuprofen is a core medicine in the World Health
Organization's "Essential
tial Drugs List",
List", which is a list of minimum medical needs for a
basic health care system [3]. Ibuprofen was derived from propionic acid by the research
arm of Boots Group during the 1960s [4].. It was discovered by Andrew RM Dunlop,
with colleagues Stewart Adams, John Nicholson, Jeff Wilson & Colin
Colin Burrows and was
patented in 1961. The drug was launched as a treatment for rheumatoid arthritis in the
United Kingdom in 1969, and in the United States in 1974. Dr. Adams initially tested
his drug on a hangover.
hangover He was subsequently awarded an OBE in 1987. Boots was
awarded the Queen's Award for Technical Achievement for the development
develo
of the drug
in 1987 [5].
51
Non-steroidal anti-inflammatory drugs such as ibuprofen work by inhibiting the enzyme
cyclooxygenase (COX), which converts arachidonic acid to prostaglandin H2 (PGH2).
PGH2, in turn, is converted by other enzymes to several other prostaglandins (which are
mediators of pain, inflammation, and fever) and to thromboxane A2 (which stimulates
platelet aggregation, leading to the formation of blood clots). Like aspirin, indometacin,
and most other NSAIDs, ibuprofen is considered a non-selective COX inhibitor—that
is, it inhibits two isoforms of cyclooxygenase, COX-1 and COX-2. The analgesic,
antipyretic, and anti-inflammatory activity of NSAIDs appears to be achieved mainly
through inhibition of COX-2, whereas inhibition of COX-1 would be responsible for
unwanted effects on platelet aggregation and the gastrointestinal tract [6]. However, the
role of the individual COX isoforms in the analgesic, anti-inflammatory, and gastric
damage effects of NSAIDs is uncertain and different compounds cause different degrees
of analgesia and gastric damage [7].
Fig. 3-2: Paracetamol or acetaminophen.
Paracetamol or acetaminophen is a widely used over-the-counter analgesic (pain
reliever) and antipyretic (fever reducer). It is commonly used for the relief of fever,
headaches, and other minor aches and pains, and is a major ingredient in numerous cold
and flu remedies. In combination with non-steroidal anti-inflammatory drugs (NSAIDs)
and opioid analgesics, paracetamol is used also in the management of more severe pain
(such as postoperative pain) [8]. While generally safe for human use at recommended
doses (1000 mg per single dose and up to 4000 mg per day for adults, up to 2000 mg per
day if drinking alcohol [9], acute overdoses of paracetamol can cause potentially fatal
liver damage and, in rare individuals, a normal dose can do the same; the risk is
heightened by alcohol consumption. Paracetamol toxicity is the foremost cause of acute
liver failure in the Western world, and accounts for most drug overdoses in the United
States, the United Kingdom, Australia and New Zealand [9-12]. Paracetamol is derived
from coal tar, and is part of the class of drugs known as “aniline analgesics”; it is the
only such drug still in use today [13]. It is the active metabolite of phenacetin, once
popular as an analgesic and antipyretic in its own right, but unlike phenacetin and its
combinations, paracetamol is not considered to be carcinogenic at therapeutic doses
[14]. The words acetaminophen (used in the United States, Canada and Hong Kong [15]
and paracetamol (used elsewhere) both come from chemical names for the compound:
para-acetylaminophenol and para-acetylaminophenol. In some contexts, it is simply
abbreviated as APAP, for N-acetyl-para-aminophenol.
52
Acetanilide was the first aniline derivative serendipitously found to possess analgesic as
well as antipyretic properties, and was quickly introduced into medical practice under
the name of Antifebrin by A. Cahn and P. Hepp in 1886 [16]. But its unacceptable toxic
effects, the most alarming being cyanosis due to methemoglobinemia, prompted the
search for less toxic aniline derivatives. Harmon Northrop Morse had already
synthesized paracetamol at Johns Hopkins University via the reduction of p-nitrophenol
with tin in glacial acetic acid in 1877 [17, 18] but it wasn't until 1887 that clinical
pharmacologist Joseph von Mering tried paracetamol on patients. In 1893, von Mering
published a paper reporting on the clinical results of paracetamol with phenacetin,
another aniline derivative [19]. Von Mering claimed that, unlike phenacetin,
paracetamol had a slight tendency to produce methemoglobinemia. Paracetamol was
then quickly discarded in favor of phenacetin. The sales of phenacetin established Bayer
as a leading pharmaceutical company [20]. Overshadowed in part by aspirin, introduced
into medicine by Heinrich Dreser in 1899, phenacetin was popular for many decades,
particularly in widely advertised over-the-counter “headache mixtures,” usually
containing phenacetin, an aminopyrine derivative or aspirin, caffeine, and sometimes a
barbiturate. Paracetamol consists of a benzene ring core, substituted by one hydroxyl
group and the nitrogen atom of an amide group in the para [21]. The amide group is
acetamide (ethanamide). It is an extensively conjugated system, as the lone pair on the
hydroxyl oxygen, the benzene pi cloud, the nitrogen lone pair, the p orbital on the
carbonyl carbon, and the lone pair on the carbonyl oxygen are all conjugated. The
presence of two activating groups also makes the benzene ring highly reactive toward
electrophilic aromatic substitution. As the substituents are ortho, para-directing and para
with respect to each other, all positions on the ring are more or less equally activated.
The conjugation also greatly reduces the basicity of the oxygens and the nitrogen, while
making the hydroxyl acidic through delocalisation of charge developed on the
phenoxide anion. Paracetamol is usually classified along with nonsteroidal
antiinflammatory drugs (NSAID), but is not considered one. Like all drugs of this class,
its main mechanism of action is the inhibition of cyclooxygenase (COX), an enzyme
responsible for the production of prostaglandins, which are important mediators of
inflammation, pain and fever. Therefore, all NSAIDs are said to possess antiinflammatory, analgesic (anti-pain), and antipyretic (anti-fever) properties. The specific
actions of each NSAID drug depend upon their pharmacological properties, distribution
and metabolism [22]. [Ru2(dNSAID)4Cl] and novel [Ru2(dNSAID)4(H2O)2]PF6
complexes, where dNSAID = deprotonated carboxylate from the non-steroidal antiinflammatory drugs (NSAIDs), respectively: ibuprofen, Hibp and aspirin, Hasp;
naproxen, Hnpx and indomethacin, Hind, have been prepared and characterized by
optical spectroscopic methods. All of the compounds exhibit mixed valent Ru2(II, III)
cores where metal–metal bonds are stabilized by four drug-carboxylate bridging ligands
in paddlewheel type structures [23] (Fig. 3-3). The diruthenium complexes and their
parent NSAIDs showed no significant effects for Hep2 human larynx or T24/83 human
bladder tumor. In contrast, the coordination of Ru2(II, III) core led to synergistic effects
that increased significantly the inhibition of C6 rat glioma proliferation in relation to the
53
organic NSAIDs naproxen and ibuprofen. The possibility that the complexes Ru2-ibp
and Ru2-npx may exert effects (anti-angiogenic and anti-matrix metalloprotease) that
are similar to those exhibited by NAMI-A opens new horizons for in vivo C6 glioma
model studies.
Fig. 3-3: Ibuprofen Coordination mode.
Diruthenium compounds of Hipb, Hasp, Hnpx and Hind NSAID drugs exhibited
paddlewheel structures with mixed valent Ru2(II, III) cores containing metal–metal
bonds stabilized by four drug-carboxylate bridging ligands. No significant effects were
found for the complexes and their parent NSAIDs in the Hep2 human larynx or the
T24/83 human bladder tumor. However, the coordination of the Ru2(II, III) core led to a
synergistic effect that increased significantly the C6 rat glioma cell antiproliferative
activity of naproxen and ibuprofen drugs. The development of novel drugs with marked
effect on glioma cell proliferation, which are also potent inhibitors of COX2, is an
important new avenue for future research related to the use of chemotherapy for glioma
treatment. The possibility that the diruthenium complexes of ibuprofen and naproxen
may exert effects (anti-angiogenic and antimatrix metalloprotease) that are similar to
those exhibited by NAMI-A opens new horizons for in vivo C6 glioma model studies.
Mesoporous silica (MS) was synthesised using amphiphilic PEO–PPO–PEO surfactant
(Pluronic F127) [24]. This chemically stable matrix composed of micropores and
mesopores was used as host system for two bactericidal zinc(II) complexes of distinct
structure types. The composite materials were characterised by thermogravimetry
(TGA), IR spectroscopy, X-ray diffraction (XRD), N2 adsorption, transmission electron
microscopy (TEM) and scanning electron microscopy (SEM). Different loadings were
achieved for the respective complexes. Their values were comparable with those
obtained by incorporation of ibuprofen into MCM-41. The correlation of the results of
XRD, nitrogen adsorption/desorption, X-ray structural analysis of the complexes and
their interactions with the silica walls is discussed in the paper (Fig. 3-4). Finally, the
54
time dependence of the release of the complexes from the mesoporous system was
investigated.
Fig. 0-4: Ibuprofen complexes with Zn.
SOD activity of the diaryl substituted heterocyclic COX-2 inhibitor, viz. oxaprozin [25],
is synergistically enhanced upon copper conjugation compared to analogous copper
compounds of established COX-1 inhibitors like aspirin and ibuprofen. A ‘‘paddle
wheel’’ structure is reported for the dimeric copper complex of oxaprozin (Fig. 3-5).
Fig. 0-5: Dimeric copper complex of oxaprozin.
55
Three new vanadyl(IV) complexes with non-steroidal anti-inflammatory drugs,
Ibuprofen, Naproxen, and Tolmetin, were synthesized and characterized by means of
elemental analysis, UV–vis, diffuse reflectance and IR spectroscopies,as well as their
magnetic behavior [26]. The biological activity of these vanadium compounds was
tested on two osteoblast-like cells in culture through a proliferation bioassay. Neither
Tolmetin nor Tol-VO af fected the UMR106 osteosarcoma cell growth. In non
transformed cells, the complex inhibits cell proliferation in a manner dependent on the
concentration. This effect was similar to that induced by VO(IV). Ibu-VO was a
stimulatory agent at low concentrations for both cell lines. However, this complex was
cytotoxic at high doses for MC3T3E1 cells. On the other hand, Nap-VO only stimulated
MC3T3E1 growth at the lower doses tested without induction of proliferation in
UMR106 cells. Above 50 mM, this complex was cytotoxic to both cell lines.
Complexes of Zn(II), Cd(II) and Pt(II) metal ions with the anti-inflammatory drugs, 1methyl-5-(p-toluoyl)-1H-pyrrole-2-acetic acid (Tolmetin), a-methyl-4-(2-methylpropyl)
benzeneacetic acid (Ibuprofen), 6-methoxy-a- ethylnaphthalene-2-acetic acid
(Naproxen) and 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid
(indomethacin) have been synthesized and characterized [27]. In the structurally
characterized Cd(naproxen)2 complex the anti-inflammatory drug acts as bidentate
chelate ligand coordinatively bound to metal ions through the deprotonated carboxylate
group. Crystal data for [C32H26O8Cd], orthorhombic, space group P22121, a=5.693(2)
(Ao), b= 8.760(3) (Ao), C= 30.74(1) (Ao), V=1533(1) Ao, Z= 2. Antibacterial and
growth inhibitory activity is higher than that of the parent ligands or the platinum(II)
diamine compounds (Fig. 3-6).
Fig. 0-6: Ibuprofen Complexes with Cd.
A synthetic investigation of copper(II) ibuprofenate (Ibup) (Fig. 3-7) addition
compounds with 2,2' –bipyridine (bpy), I,IO-phenanthroline (phen) and 2,9-dimethylI,10-phenanthroline (dmph) has led to the isolation of dinuclear adducts of the forms
[Cu(lbup)2(bpy)2. 4H2O and [Cu(Ibup)2(phen)]2 and a mononuclear adduct
Cu(lbup)2(dmph) [28]. Spectroscopic data for adducts are consistent with a dinuclear
structure with two CuN2O2+O chromophors. Each copper is coordinated with two
56
ibuprofenate bridges, a terminal diimine molecule and a monodentate ibuprofenate
group complete five-coordination at each metal atom. Spectroscopic data for adduct are
consistent with a mononuclear structure having a much distorted squarepyramidal
CuN2O2+O chromophore. The CuII atom is coordinated to two nitrogen atoms from a
chelating dmph ligand, two carboxylic oxygens of a bidentate ibuprofenate ion and an
oxygen atom of a monodentate carboxylic group of a second ibuprofenate ion. The
reduction of adduct by ascorbic acid produced stable red copper(I) complex of the form
[Cu(dmp)2] (Ibup). Spectral data of this adduct indicated that the cation has distorted
tetrahedral geometry about the copper atom. The effect of adducts on the rate of
hydrolysis of bis(p-nitrophenyl) phosphate (BNPP) have been examined in aqueous
methanol solution at 70e and pH 7.4.
Fig. 0-7: Copper(II) ibuprofenate Complexes.
The preparation of dimolybdenum(I1) complexes with tilt drug ibuprofen has
been investigated (Fig. 3-8). The compound [Mo2(R-C13H17O2-(S- C13H17O2 ] has been
structurally characterized [29]. It crystallizes in the monoclinic space group P21/c, with
unit cell dimensions a = 5.5307( 6) Ao, b = 30.634(5) Ao, c= 15.234(2) Ao, β= 91.87(
8)°, V= 2579.8(6)Ao, Z= 2. The asymmetric unit consists of half of the molecule which
resides on a crystallographic inversion center. The configurations of the four chiral
ligands around the dimetal unit follow the cyclic order RRSS. The Mo--Mo distance is
2.085(2) Ao.
57
Fig. 0-8: Dimolybdenum(II) complexes with ibuprofen.
Two mononuclear coppenII) ibuprofenate adducts with imidazole or 2methylimidazole and two binuclear coppenII) ibuprofenate adducts with metronidazole
or caffeine have been prepared and characterized [30]. Elemental analyses, UV -VIS,
IR, EPR, and magnetic moment data for imidazole or 2-methylimidazole adducts are
consistent with mononuclear square planar complexes that contain two ibuprofenato
ligands and two N-containing imidazole ligands to give essentially a CuO2N2
chromophore. The above data for metronidazole or caffeine adducts are consistent with
a binuclear structure as found for copperII) acetate monohydrate and other coppenII)
carboxylate dimers. In these complexes four carboxylate groups are bridging two
coppenIl) atoms, and two added bases coordinated at axial positions to form CuO4N
chromophore around each copper. The catecholase-mimetic catalytic activities of the
complexes have been determined by monitoring the formation of o-quinone from
catechol. The catalytic activities of the mononuclear complexes are lower than those of
the binuclear copperII) ibuprofenate or its metronidazole or caffeine mono-adducts.
Tridendate ligands have been derived from the amino acids lysine, methionine,
methionine sulfoxide, and homomethionine by dimethylation at nitrogen and reduction
of the carboxyl group followed by substitution of hydroxyl by the diphenylphosphino
group [31]. These ligands are effective in promoting the Nio or Pdo catalyzed cross
coupling of the Grignard reagent of l-chloro-1-phenylethane with vinyl bromide. The
enantiomeric excesses found for coupling product formed in the presence of these
ligands exceed those expected on the grounds solely of a steric effect of the amino acid
side chain. A special effect of the heteroatom in the side chain is indicated. X-ray
diffraction studies of the PdCl, complexes of the ligands derived from methionine and
homomethionine confirm the expected coordination of the transition metal atom by the
58
phosphino and amino centers and reveal that there is no significant ligation of sulfide in
these dipositive cations.
Complexes of Paracetamol with various metal ions such as, Cu(II), Zn(II) or
Fe(II) ions of ratio 2:1, respectively (Fig. 3-9), have been prepared and their
structurehas been confirmed by elemental analysis, atomic absorption spectra, IR
spectra and 1H-NMR spectra and finally it can be concluded that the structure of the
complexes has C2h point group symmetry in which two PA molecules are chelated to
any one of the metal ions, Cu(II), Zn(II) and Fe(II) ions [32].
Fig. 3-9: Structure of PAracetamole complexes.
The kinetics of the oxidation of ruthenium(III)- and osmium(VIII)-catalysed
oxidation of paracetamol by diperiodatoargentate(III) (DPA) in aqueous alkaline
medium at a constant ionic strength of 0.10 mol dm-3 was studied
spectrophotometrically [33]. The reaction between DPA and paracetamol in alkaline
medium exhibits 2:1 stoichiometry in both catalysed reactions (DPA:PAM) (Fig. 3-10).
The main products were identified by spot test, IR, NMR and GC–MS. Probable
mechanisms are proposed and discussed. The activation parameters with respect to the
slow step of the mechanism are computed and discussed and thermodynamic quantities
are also calculated. It has been observed that the catalytic efficiency for the present
reaction is in the order of Os(VIII) > Ru(III). The active species of catalyst and oxidant
have been identified.
59
Fig. 3-10: Structure of Ru and Os Paracetamol complexes.
The comparative study of Ru(III)- and Os(VIII)-catalysed oxidation of paracetamol by
diperiodatoargentate(III) was studied. Oxidation products were identified. Among
various species of Ag(III) in alkaline medium, monoperiodatoargentate(III) is
considered to be the active species for the title reaction. The active species of Ru(III) is
found to be [Ru(H2O)5OH]2+ and that for Os(VIII) is [OsO4(OH)2]2-. Activation
parameters were evaluated for both catalysed and uncatalysed reactions. Catalytic
constants and the activation parameters with reference to the catalyst were also
computed. The catalytic efficiency is Ru(III) < Os(VIII). Elena V. Boldyreva
summarized experimental X-ray diffraction and IR-spectroscopic data on the effect of
pressure on a number of molecular and ionic-molecular crystals: monoclinic (I) and
orthorhombic (II) polymorphs of paracetamol, fenacetin, monoclinic (a) and trigonal (g)
polymorphs of glycine, p-benzoquinone, Co(III)-nitro- and nitrito-pentaammine
complexes, and sodium oxalate [34]. Special attention is paid to the role of
intermolecular interactions, in particular hydrogen bonds, in the anisotropy of structural
distortion (Fig. 3-11). For several compounds, the distortions induced by high-pressure
and low-temperature are compared.
60
Fig. 3-11: Packing diagram of some Paracetamol complexes.
Pressure-induced polymorphic transitions attract much more attention than
continuous structural changes in the same polymorph. However, the latter can also be
valuable not only to predict the direction of a polymorphic transformation and to
understand its mechanism but also to find parameters characterizing intermolecular
interactions in crystals, in particular hydrogen bonds of various types [35]. This
information can find various applications, ranging from crystal engineering, polymorph
prediction and solid-state reactivity to the prediction of secondary and ternary structures
of biopolymers and their response to various external actions.
It was found that polyvinylpyrrolidone (PVP) is an effective additive during
crystallization of paracetamol and significantly influenced the crystallization and crystal
habit of paracetamol [36]. These effects were attributed to adsorption of PVP onto the
surfaces of growing crystals. It was found that the higher molecular weights of PVP
(PVP 10 000 and PVP 50 000) were more effective additives than lower molecular
weight PVP (PVP 2000). Paracetamol particles obtained in the presence of 0.5% w:v of
PVP 10 000 or PVP 50 000 had near spherical structure and consisted of numerous rodshaped microcrystals which had agglomerated together. Particles obtained in the
presence of PVP 2000 consisted of fewer microcrystals. Differential scanning
calorimetry (DSC) and X-ray powder diffraction (XPD) experiments showed that
paracetamol particles, crystallized in the presence of PVP, did not undergo structural
modifications. By increasing the molecular weight and: or the concentration of PVP in
the crystallization medium the amount of PVP incorporated into the paracetamol
particles increased. The maximum amount of PVP in the particles was 4.32% w:w.
After a large drug scanning [36], the system Luminol–H2O2–Fe(CN)63- is proposed for
first time for the indirect determination of paracetamol. The method is based on the
61
oxidation of paracetamol by hexacyanoferrate (III) and the subsequent inhibitory effect
on the reaction between luminol and hydrogen peroxide. The procedure resulted in a
linear calibration graph over the range 2.5–12.5 mg ml-1 of paracetamol with a sample
throughput of 87 samples h-1. The influence of foreign compounds was studied and, the
method was applied to determination of the drug in three different pharmaceutical
formulations.
REFERENCES
1- Anonymous (1990). Cancer pain relief and palliative care; report of a WHO expert
committee. World Health Organization Technical Report Series, 804. Geneva,
Switzerland: World Health Organization. pp. 1–75. ISBN 924120804X.
2- Dworkin RH, Backonja M, Rowbotham MC, et al. (2003). "Advances in
neuropathic pain: diagnosis, mechanisms, and treatment recommendations". Arch.
Neurol. 60 (11): 1524–34. doi:10.1001/archneur.60.11.1524. PMID 14623723.
http://archneur.ama-assn.org/cgi/content/full/60/11/1524.
3- "WHO Model List of Essential Medicines" (PDF). World Health Organization.
March 2005. http://whqlibdoc.who.int/hq/2005/a87017_eng.pdf. Retrieved 2006-0312.
4- Adams SS (April 1992). "The propionic acids: a personal perspective". J Clin
Pharmacol 32 (4): 317–23. PMID 1569234. http://jcp.sagepub.com/cgi/
reprint/32/4/317.
5- Lambert, Victoria (2007-10-08). "Dr Stewart Adams: 'I tested ibuprofen on my
hangover' - Telegraph". The Daily Telegraph (London). http://www.telegraph
.co.uk/health/main.jhtml?xml=/health/2007/10/08/hadams108.xml. Retrieved 200801-20.
6- Rao P, Knaus EE (2008). "Evolution of nonsteroidal anti-inflammatory drugs
(NSAIDs): cyclooxygenase (COX) inhibition and beyond". J Pharm Pharm Sci 11
(2): 81s–110s. PMID 19203472.
7- Kakuta H, Zheng X, Oda H, et al. (April 2008). "Cyclooxygenase-1-selective
inhibitors are attractive candidates for analgesics that do not cause gastric damage.
design and in vitro/in vivo evaluation of a benzamide-type cyclooxygenase-1
selective inhibitor". J. Med. Chem. 51 (8): 2400–11. doi:10.1021/jm701191z.
PMID 18363350
8- Control of Pain in Adults with Cancer Sign Guidelines 106 Section 6.1 and 7.1.1.
9- Acetaminophen www.drug.com/acetaminophen.html
10- Daly FF, Fountain JS, Murray L, Graudins A, Buckley NA (2008). "Guidelines for
the management of paracetamol poisoning in Australia and New Zealand—
explanation and elaboration. A consensus statement from clinical toxicologists
consulting to the Australasian poisons information centres". Med. J. Aust. 188 (5):
296–301. PMID 18312195.
11- Khashab M, Tector AJ, Kwo PY (2007). "Epidemiology of acute liver failure". Curr
Gastroenterol Rep 9 (1): 66–73. doi:10.1007/s11894-008-0023-x. PMID 17335680.
62
12- Hawkins LC, Edwards JN, PI (2007). "Impact of restricting paracetamol pack sizes
on paracetamol poisoning in the United Kingdom: a review of the literature". Drug
Saf 30 (6): 465–79. doi:10.2165/00002018-200730060-00002. PMID 17536874.
13- Bertolini A, Ferrari A, Ottani A, Guerzoni S, Tacchi R, Leone S (2006).
"Paracetamol: new vistas of an old drug". CNS drug reviews 12 (3–4): 250–75.
doi:10.1111/j.1527-3458.2006.00250.x. PMID 17227290.
14- Bergman K, Müller L, Teigen SW (1996). "The genotoxicity and carcinogenicity of
paracetamol: a regulatory (re)view". Mutat Res 349 (2): 263–88. doi:10.1016/00275107(95)00185-9. PMID 8600357.
15- Bradley, N (1996). "BMJ should use "paracetamol" instead of "acetaminophen" in
its index". BMJ 313 (7058): 689.
16- Cahn, A; Hepp P (1886). "Das Antifebrin, ein neues Fiebermittel". Centralbl. Klin.
Med. 7: 561–64.
17- Morse
HN
(1878).
"Ueber
eine
neue
Darstellungsmethode
der
Acetylamidophenole". Berichte der deutschen chemischen Gesellschaft 11 (1): 232–
233. doi:10.1002/cber.18780110151.
18- Milton Silverman, Mia Lydecker, Philip Randolph Lee (1992). Bad Medicine: The
Prescription Drug Industry in the Third World. Stanford University Press. pp. 88–
90. ISBN 0804716692.
19- Von Mering J. (1893) Beitrage zur Kenntniss der Antipyretica. Ther Monatsch 7:
577–587.
20- Sneader, Walter (2005). Drug Discovery: A History. Hoboken, N.J.: Wiley. p. 439.
ISBN 0471899801.
21- Bales, JR; Nicholson JK, Sadler PJ (May 1, 1985). "Two-dimensional proton
nuclear magnetic resonance "maps" of acetaminophen metabolites in human urine".
Clinical Chemistry 31 (5): 757–762. PMID 3987005.
22- Ottani A, Leone S, Sandrini M, Ferrari A, Bertolini A (2006). "The analgesic
activity of paracetamol is prevented by the blockade of cannabinoid CB1 receptors".
Eur. J. Pharmacol. 531 (1–3): 280–1. doi:10.1016/j.ejphar.2005.12.015.
PMID 16438952.
23- Geise Ribeiro , Marcel Benadiba , Alison Colquhoun , Denise de Oliveira Silva,
Polyhedron 27 (2008) 1131–1137.
24- V. Zelenak, V. Hornebecq, P. Llewellyn, Microporous and Mesoporous Materials
83 (2005) 125–135.
25- Sabari Dutta, Subhash Padhye, Vickie Mckee, Inorganic Chemistry
Communications 7 (2004) 1071–1074.
26- S.B. Etcheverry, D.A. Barrio, A.M. Cortizoa, P.A.M. Williams, Journal of Inorganic
Biochemistry 88 (2002) 94–100.
27- Catherine Dendrinou-Samara, Georgia Tsotsou, Loucia V. Ekateriniadou , Alekos
H. Kortsaris , Catherine P. Raptopoulou , Aris Terzis , Dimitris A. Kyriakidis ,
Dimitris P. Kessissoglou, Journal of Inorganic Biochemistry 71 (1998) 171-179.
28- A. Latif Abuhijleh, polyhedron Vol. 16. No.4. pp. 733 740.1997.
29- F. Albert Cotton , Denise de O. Silva, InorganieaChimica Acta 249 (1996) 57-61.
63
30- A. Latif Abuhijleh, Journal of Inorganic Biochemistry, 55,255-262 (1994).
31- Graham Cross , Bindert K. Vriesema, Gerd Boven, Richard M. Kellogg, Journal of
Organomeiallic Chemistry, 370 (1989) 357-381.
32- A.S. El-Shahawy, S.M. Ahmed, N.Kh. Sayed, Spectrochimica Acta Part A 66
(2007) 143–152.
33- Kiran T. Sirsalmath, Chanabasayya V. Hiremath, Sharanappa T. Nandibewoor,
Applied Catalysis A: General 305 (2006) 79–89.
34- Elena V. Boldyreva, Journal of Molecular Structure 647 (2003) 159–179.
35- Hadi A. Garekani , James L. Ford , Michael H. Rubinstein, Ali R. RajabiSiahboomi, International Journal of Pharmaceutics 208 (2000) 87–99.
36- Gregorio Alapont , L. Lahuerta Zamora , J. Martıńez Calatayud, Journal of
Pharmaceutical and Biomedical Analysis 21 (1999) 311–317.
64
CHAPTER 4
4-1- Anti-rheumatic
rheumatic Drugs
Antirheumatic drugs are drugs used to treat rheumatoid arthritis.
arthritis Rheumatoid
arthritis is a progressive form of arthritis that has devastating effects on joints and
general health. It is classified as an auto-immune
auto immune disease, because the disease is caused
by the body's own immune system acting against the body itself. Symptoms
Sym
include
painful, stiff, swollen joints, fever, fatigue, and loss of appetite. In recent years, there
has been a change in attitude concerning the treatment of rheumatoid arthritis.
Physicians
hysicians now use Disease Modifying Anti-Rheumatic
Anti Rheumatic Drugs (DMARDs) early in the
history of the disease and are less inclined to wait for crippling stages before resorting to
the more potent drugs. Fuller understanding of the side-effects
side effects of non-steroidal
non
antiinflammatory drugs (NSAIDs) has also stimulated reliance on other types of
antirheumatic drugs. The major classes of antirheumatic drugs include: Nonsteroidal
Anti-Inflammatory
Inflammatory Drugs (NSAIDs. Drugs belonging to this class bring symptomatic
relief of bothh inflammation and pain,, but have a limited effect on the progressive bone
and cartilage loss associated with rheumatoid arthritis. They act by slowing the body's
production of prostaglandins.
prostaglandins. Common NSAIDs include: ibuprofen (Motrin, Nuprin or
Advil), naproxen (Naprosyn, Aleve) and indomethacin (Indocin). These drugs are very
powerful antiinflammatory agents. They are the synthetic analogs of cortisone,
produced by the body. Corticosteroids are used to reduce inflammation and suppress
activity of the immune system. The most commonly prescribed are prednisone and
dexamethasone. Disease Modifying Anti-Rheumatic
Anti Rheumatic Drugs (DMARDs). DMARDs
influence the disease process itself and do not only treat symptoms,
symptoms, hence their name.
DMARDs also have anti-inflammatory
anti inflammatory effects, and most were borrowed from the
treatment of other diseases, such as cancer and malaria.. Antimalarials DMARDs include
chloroquine (Aralen) and hydroxychloroquine (Plaquenil). Powerful DMARDs include:
methotrexate (Rheumatrex), sulfasalazine, cyclosporine, azathioprine (Imuran) and
cyclophosphamide (Cytoxan),
toxan), azathioprine, sulfasalazine, penicillamine, and organic
gold compounds such as aurothioglucose (Solganol), gold sodium thiomalate (Aurolate)
and auranofin (Ridaura). Slow-Acting
Acting Antirheumatic Drugs (SAARDs). SAARDs are a
special class of DMARDs and the effect of these drugs is slowing acting and not so
quickly apparent as that of the NSAIDs. Examples are hydroxychloroquine and
aurothioglucose [1].
Fig. 4-1: Diclofenac structure.
structure
65
Diclofenac Fig. 4-1, (marketed as Voltaren and under a number of other trade
names, see below) is a non-steroidal anti-inflammatory drug (NSAID) taken to reduce
inflammation and as an analgesic reducing pain in conditions such as arthritis or acute
injury. It can also be used to reduce menstrual pain, dysmenorrhea. The name is derived
from its chemical name: 2-(2,6-dichloranilino)phenylacetic acid. Diclofenac originated
from Ciba-Geigy (now Novartis) in 1973 [2]. Diclofenac was first introduced in the UK
in 1979 [3,4]. The exact mechanism of action is not entirely known, but it is thought
that the primary mechanism responsible for its anti-inflammatory, antipyretic, and
analgesic action is inhibition of prostaglandin synthesis by inhibition of cyclooxygenase
(COX) and it appears to inhibit DNA synthesis [5, 6]. Inhibition of COX also decreases
prostaglandins in the epithelium of the stomach, making it more sensitive to corrosion
by gastric acid. This is also the main side effect of diclofenac. Diclofenac has a low to
moderate preference to block the COX2-isoenzyme (approximately 10-fold) and is said
to have therefore a somewhat lower incidence of gastrointestinal complaints than noted
with indomethacin and aspirin. The action of one single dose is much longer (6 to 8
hours) than the very short half-life that the drug indicates. This could partly be due to a
particular high concentration achieved in synovial fluids [5]. Diclofenac may also be a
unique member of the NSAIDs. There is some evidence that diclofenac inhibits the
lipoxygenase pathways, thus reducing formation of the leukotrienes (also proinflammatory autacoids). There is also speculation that diclofenac may inhibit
phospholipase A2 as part of its mechanism of action. These additional actions may
explain the high potency of diclofenac – it is the most potent NSAID on a broad basis.
There are marked differences among NSAIDs in their selective inhibition of the two
subtypes of cyclo-oxygenase, COX-1 and COX-2. Much pharmaceutical drug design
has attempted to focus on selective COX-2 inhibition as a way to minimize the
gastrointestinal side effects of NSAIDs like aspirin. In practice, use of some COX-2
inhibitors due to their adverse effects has led to massive numbers of patient family
lawsuits alleging wrongful death by heart attack, yet other significantly COX-selective
NSAIDs like diclofenac have been well-tolerated by most of the population [6].
Besides the well-known and often cited COX-inhibition, a number of other
molecular targets of diclofenac have recently been identified which could contribute to
its pain-relieving actions. These include:
Blockade of voltage-dependent sodium channels (after activation of the channel,
diclofenac inhibits its reactivation also known as phase inhibition. Blockade of acidsensing ion channels (ASICs). Positive allosteric modulation of KCNQ- and BKpotassium channels (diclofenac opens these channels, leading to hyperpolarization of
the cell membrane).
66
Fig. 4-2: Indomethacin structure.
structure
Indometacin Fig. 4-2, or indomethacin is a non-steroidal anti--inflammatory drug
commonly used to reduce fever, pain, stiffness, and swelling.. It works by inhibiting the
production of prostaglandins,
prostaglandins, molecules known to cause these symptoms. It is marketed
under many trade names, including Indocin, Indocid, Indochron E-R,
E R, and Indocin-SR.
Indocin
Indomethacin has also been used clinically to delay premature labor,
labor reduce amniotic
fluid in polyhydramnios
ios, and to close patent ductus arteriosus.. Indomethacin is a potent
drug with many serious side effects and should not be considered an analgesic for minor
aches
ches and pains or fever. The drug is more potent than aspirin,, but is not a better
analgesic. In mild to moderate pain a standard oral dose of indomethacin proved as
effective as 600 mg aspirin.
aspiri Indomethacin was discovered in 1963 [7] and it was first
approved for use in the U.S. by the Food and Drug Administration in 1965. Its
mechanism of action, along with several other NSAIDs that inhibit COX, was described
in 1971 [8].
Indomethacin is a nonselective inhibitor of cyclooxygenase (COX) 1 and 2,
enzymes that participate in prostaglandin synthesis from arachidonic acid.
Prostaglandins are hormone-like
hormone like molecules normally found in the body, where they
have a wide variety of effects, some of which lead to pain, fever, and inflammation.
Prostaglandins also cause uterine contractions in pregnant women. Indomethacin is an
effective tocolytic agent, able to delay premature labor by reducing uterine contractions
through inhibition of PG synthesis in the uterus and possibly through calcium channel
blockade [9].
Indomethacin has two additional modes of actions with clinical importance: It
inhibits motility of polymorphonuclear leukocytes, similar to colchicine.
colchicine It uncouples
oxidative phosphorylation in cartilaginous (and hepatic) mitochondria, like salicylates.
These additional effects account as well for the analgesic and the anti-inflammatory
anti
properties. Indomethacin readily crosses the placenta,, and can reduce fetal urine
production to treat polyhydramnios. It does so by reducing renal blood flow and
increasing renal vascular resistance, possibly by enhancing the effects of vasopressin on
the fetal kidneys.
Copper(II) complexes of diclofenac with interesting anti-inflammatory
anti inflammatory profiles have
been prepared and studied by infrared and electronic spectroscopy. In the solid state and
in polar and coordinating solvents, all the complexes are solvated binuclear carboxylatocarboxylato
bridged complexes, [Cu(L)2(S)]2, where L is monodeprotonated diclofenac and S is the
67
axially bonded solvent [10]. The effect of the copper(II) complexes on the in vitro DNA
strand breakeage was studied by agarose gel electrophoresis. Relaxation or double
stranded scissions of pDNA were observed leading to the formation of linear pDNA.
Treatment of pDNA with high concentrations of these compounds caused a
disappearance of pDNA. For the parent drug, sodium diclofenac, no effect on the pDNA
was observed. This study presents some indications that the binuclear copper(II)
complexes, [Cu(L)2(S)]2, could have some relevance in the treatment of tumor cell lines
(Fig. 4-3).
Fig. 4-3: Diclofenac Complexation Mode.
Trans-[Co(en)2(NO2)2]X complexes, where X¼C12H25SO4, C6H2N3O7, C14H10Cl2NO2
and C7H4NSO3, have been synthesized by slowly mixing aqueous solutions of transdinitrobis(ethylenediamine)cobalt(III) nitrate and sodium dodecyl sulfate, picrate,
diclofenac and saccharinate, respectively, at a 1 : 1 mol ratio [11]. Good crystals of
trans-dinitrobis
(ethylenediamine)cobalt(III)
saccharinate
monohydrate,
[Co(en)2(NO2)2](C7H4NSO3).H2O, were obtained. The salt is orthorhombic, space group
P21212, with a=21.553(2), b=8.503(1), c=10.238(1)A˚ , Z=4, V¼1876.3(3)A˚3,
R1=0.0286 and wR2=0.0727. A structure determination revealed an ionic structure
consisting of discrete [Co(en)2(NO2)2] cations and [C7H4SO3N]– anions.
In the exploration of cationic cobaltammine [trans-Co(en)2(NO2)2]+ as an anion receptor
[12], binding with oxoanions diclofenac and chlorate ions has been investigated. Yellow
crystals of [trans-Co(en)2(NO2)2]C14H10Cl2NO2. 2H2O, and [trans-Co(en)2(NO2)2]ClO3,
have been obtained from a mixture of trans-[bis(ethylenediamine) dinitrocobalt(III)]
nitrate solution with sodium diclofenac and sodium chlorate, respectively (Fig. 4-4), in
aqueous medium. The products were characterised by elemental analyses, IR, UV/vis,
1
H and 13C-NMR spectroscopy. Single crystal X-ray structure determinations revealed
that electrostatic forces of attraction besides second sphere hydrogen bonding
interactions stabilize the crystal lattice. Oxygen atoms of the halate and carboxylate
group in diclofenac ions act as hydrogen bond acceptors thereby forming N-Hen.......O
68
bonds. The results show that [trans-Co(en)2(NO2)2]+ is a promising anion receptor for
the weakly coordinating halate and diclofenac ions in aqueous medium. Solubility
measurements indicate that the affinity of cationic cobaltammine [trans-Co(en)2(NO2)2]+
is greater for diclofenac than for the chlorate ion.
Fig. 4-4: Anion receptor of cationic cobaltammine [trans-Co(en)2(NO2)2]+
The structure of the centro symmetric dimeric copper(II) title compound,
[Cu2(C14H10Cl4NO2)4(C3H6O).C2H4O (Fig. 4-5), has peen determined and compared
with the structures of analogous O-bridged Cu II dimmers [13]. Polarographic
experiments on aqueous solutions containing a mixture of the Cu II ion and diclofenac
have been used to detennine both the formation constant [1(1)x108] and the solubility
product [2(1)x10-12] of the complex.
69
Fig. 4-5: Structure of [Cu2(C14H10Cl4NO2)4(C3H6O).C2H4O complex.
IR, 1H-NMR and mass spectrometric studies showed that cetirizine
dihydrochloride interacted strongly with diclofenac sodium, even when the latter was
metal bound, forming high molecular weight stable adducts. These new formations were
unaffected by the possible steric constraints that may exist because of coordination yet
did not have the power to break the formed coordinate bonds [14]. The formed ionic
bond took place between the carbonyl ion of diclofenac and the positively charged
70
piperazine ring of cetirizine, forming a ternary compound in the case of the divalent
metal clusters (Ca{(dic)2·2H2O}, Mg{(dic)2·2H2O}, Zn{(dic)2·2H2O}) and a quaternary
one with the trivalent iron cluster (Fe{dic}3·3H2O) (Fig. 4-6). IR bands assigned to
νNH, δNH and νC-N were shifted to lower frequency values in the spectra of the
complexes; thus showing that coordination took place at the NH of the diphenylamine.
TG and elemental analysis confirmed these results.
Fig. 4-6: Structure of (Ca{(dic)2·2H2O}, Mg{(dic)2·2H2O}, Zn{(dic)2·2H2O}).
[CdII2(dic)4(etOH)2(H2O) ]n [15]. The complex is polymeric, and the coordination
geometry for the two independent metal atoms is highly distorted. Cd(1) is hexacoordinated by the oxygen atoms (Cd-O, 2.407(7), 2.321(7) Ao) from a bridging
carboxylato to Cd(2), by two oxygen atoms (Cd-O,2.26(1) Ao average) from two etOH
(cis to each other), by an oxygen atom (Cd-O, 2.25(1) Ao) from a second bridging
carboxy-lato to another Cd(2) center, and from a water molecule. Cd(2) has a pentacoordination to the two oxygen atoms (Cd-O, 2.505(8), 2.282(8) Ao) from a
carboxylato, and to one oxygen atom (Cd-O,2.28(1), 2.17(1), 2.17(1)) each from three
bridging carboxylato to Cd(1). Cd(2) has a sixth very weak interaction to an oxygen
from a bridging carboxylato (2.76(1) Ao). The conformation of dic' around the O2 angle
is anti-trans (-166, -166, -174, -162o).in the four independent molecules, whereas the
conformation for the O3 angle is anti-clinal (-118, -118, -122, -125o). The analysis
reported above for the dic derivative shows that he flexibility of the dic/Hdic molecules
around the C(4)N(1) and N(l)-C(9) vectors is restricted to a rather narrow range (Fig. 47). It has been reported that the proper conformation adopted by diclofenac to inhibit
71
COXs and to rat adjuvant arthritis consists of a twisting of the two aromatic rings of
some 58-49 o, as found for the structures of the metal-dic complexes.
Fig. 4-7: Structure of Cd-diclofenac complexes.
Some new complexes of diclofenac with potentially interesting biological
activity are described [16]. The complexes of diclofenac [MnL2(H2O)],
[CoL2(H2O)2].0.5H2O, [CoL2(H2O)], [NiL2(H2O)2].2H2O, and [NiL2], were prepared by
the reaction of the sodium salt, of a potent anti-inflammatory drug with MnCl2, CoCl2
and NiCl2.6H2O. Optical, EPR, infrared and electrochemical properties of these new
complexes are reported. Both five and six-coordinated species were isolated in the solid
state for Co(II). Both four and six-coordinated species were isolated in the solid state for
Ni(II), while in DMF or MeOH solution predominant formation of sixcoordinated
species is observed for Co(II) and Ni(II) complexes. The ability of the complexes to
catalyze the oxidation of 3,5-di-tertbutyl- o-catechol to 3,5-di-tert-butyl-o-quinone was
studied by following the appearance of quinone spectrophotometrically. Correlation of
the catalytic activity of these complexes to the reduction potential is reported. Binuclear
complexes, [Cu(L)2(H2O)]2.2H2O and [CuL2(S)]2 where S is H2O, EtOH, DMSO,
(CH3)2CO and DMF, and mononuclear complexes, [MnL2(H2O)], [FeL2(H2O)2],
[CoL2(H2O)2].0.5H2O, [CoL2(H2O)], [NiL2(H2O)2].2H2O, [NiL2] and [PdL2]P2H2O, have
been characterized by spectroscopy, X-ray crystallography and electrochemical studies
(Fig. 4-8) [17]. The catalytic activity of these complexes was correlated to the reduction
potential. Some of the complexes of diclofenac exhibit very promising antiinflammatory activity and act as antioxidant compounds, a property that is absent from
diclofenac.
72
Fig. 4-8: Solvent exchange in Diclofenac complexes.
All the tested complexes except the complex of Fe(III) exhibited a strong
inhibitory effect on carrageenin-induced edema suggesting that they interfere with the
release of histamine and serotonin and/or prostaglandin syntheses. Con-A-induced
edema was inhibited by diclofenac, Cu(II), Pd(II), Fe(II), Ni(II) and Co(II) complexes
of diclofenac. The complex of Mn(II) did not inhibit significantly the con-A-induced
edema in contrast to its significant inhibition of carrageenan-induced edema. This
finding suggests that the con-Aand carrageenan-induced edemas are due, at least to
some extent, to different mediators. Complexes of diclofmac, [CuL2H2O)]2.2H2O, and
[CuL2DMF)]2 were prepared by the reaction of the sodium salt of this potent
antiinflammatory drug with CuCl2 [18]. The new symmetric binuclear copper(II)
complex [CuL2(DMF)]2 crystallizes in the monoclinic space group P21/n with cell
constants a = 10.807(1), b = 15.429(2), c = 19.360(2), fJ = 92.508(3), V = 3225(1) 13,
and Z =2 (Fig. 2-56). The structure was determined from 5456 out of a total of 5768
unique reflections. The final values for R1, WR2, and GOF for all data are 0.0602,
0.1066, and 1.030, respectively. The crystal structure consists of a binuclear quadruply
bridged neutral molecule. The four carboxylato groups from four ligands are in the
familar bidentate syn, syn 1 1 µ 2 bridging mode. The metal coordination geometry is
described as a perfect square bipyramid with water or dimethyloformamide oxygen
occupying both apical positions (Fig. 4-9). Optical, infrared, electron paramagnetic
resonance, magnetic, and electrochemical properties of these complexes are also
reported.
73
Fig. 4-9: Diclofenac CuII complexes.
[Ru2(dNSAID)4Cl] and novel [Ru2(dNSAID)4(H2O)2]PF6 complexes (Fig. 4-10),
where dNSAID= deprotonated carboxylate from the non-steroidal anti-inflammatory
drugs (NSAIDs), respectively: ibuprofen, Hibp and aspirin, Hasp; naproxen, Hnpx and
indomethacin, Hind, have been prepared and characterized by optical spectroscopic
methods [19]. All of the compounds exhibit mixed valent Ru2(II, III) cores where
metal–metal bonds are stabilized by four drug-carboxylate bridging ligands in
paddlewheel type structures. The diruthenium complexes and their parent NSAIDs
showed no significant effects for Hep2 human larynx or T24/83 human bladder tumor.
In contrast, the coordination of Ru2(II, III) core led to synergistic effects that increased
significantly the inhibition of C6 rat glioma proliferation in relation to the organic
NSAIDs naproxen and ibuprofen. The possibility that the complexes Ru2-ibp and Ru2npx may exert effects (anti-angiogenic and anti-matrix metalloprotease) that are similar
to those exhibited by NAMI-A opens new horizons for in vivo C6 glioma model
studies.
Fig. 4-10: Indomethacin Ru complexe.
74
The crystal and molecular structures of the novel compound diamminetetrakism-(O,O-indole-3-carboxylate)dicopper(II), Cu–I3CA, have been determined using
single-crystal X-ray diffraction, infrared spectroscopy and EPR methods [20]. The
crystals are monoclinic, space group P21/c, with a=9.505(2), b=7.469(1), c=23.779(5),
V=1669.1(6) A°3 and Z=2. Complex has a dinuclear molecular structure of Ci
symmetry in which the carboxyl groups of the indole-3-carboxylic acid ligands act as
bridges. The Cu–Cu distance of 2.6387(8) A°, Cu–O distances of 1.961(2) and 1.970(2)
A°, and Cu–NH3 distance of 2.188(2) A°, are typical of such dinuclear complexes (Fig.
4-11). The novel Cu–I3CA complex unit reveals a remarkable similarity in its structural
and spectroscopic features to the Cu(II) complexes of the human antiinflammatory drug,
indomethacin (a derivative of indole-3-acetic acid). The EPR and infrared spectroscopic
studies of Cu–I3CA in the solid state well support the results from X-ray analysis (Fig.
4-12). The harmonic vibrational frequencies, infrared intensities and Raman scattering
activities of the O-deprotonated indole-3-carboxylate ion (I3CAK) have been calculated
using density functional (B3LYP) method with the 6-311++G(d,p) basis set. The
potential energy distribution (PED) calculated for the ionic ligand (I3CAK) has proved
to be of great help in assigning the infrared spectrum of the title complex. The results
from natural bond orbital (NBO) analyses for I3CA-and indole-3-carboxylic acid (I3CA)
are discussed.
Fig. 4-11: ORTEP III drawing of Cu–13CA
75
Fig. 4-12: The hydrogen bonding pattern in Cu–13CA
The complexes [Me2(Indo)SnOSn(Indo)Me2]2, Bu2(Indo)SnOSn(Indo)Bu2]2,
(Fig. 4-13), where Hindo is indomethacin, have been prepared and structurally
characterized by means of 119Sn Mossbauer, vibrational, and NMR (1H and 13C)
spectroscopy
[21].
The
crystal
structures
of
the
complex
[Me2(Indo)SnOSn(Indo)Me2]2.2C4H8O2, has been determined by X-ray crystallography.
Each structure is centro-symmetric and features a central rhombus Sn2O2 unit with two
additional tin atoms linked at the O atoms. Pairs of tin atoms are bridged by bidentate
carboxylate ligands and by a monoatomic bridging oxygen. C-H π , π π, stacking
interactions, inter and intramolecular hydrogen bonds.
Fig. 4-13: Structure of [Me2(Indo)SnOSn(Indo)Me2]2.2C4H8O2
76
A discrete variational-Xa (DV-Xa) method was applied to elucidate the
formation of C–O–Si bridging bonds, produced when a silanol group of SiO2 comes
close enough to react with a carboxyl group of indomethacin (IM) [22]. A decrease in
the coordination number (CN) of oxygen atoms per silicon atom at the SiO2 surface
increased the net charge (NC) of the silanolic hydrogen atom and decreased the bond
overlap population (BOP) between the silanolic oxygen and hydrogen atoms. These
changes favored the formation and stabilization of C–O–Si bridging bonds with
simultaneous dehydration. The computational results agreed well with our previous
experimental study of a ground indomethacin–SiO2 mixture to obtain a better solid
dispersion of the drug (Fig. 4-14).
Fig. 4-14: indomethacin–SiO2 strucure.
The crystal and molecular structures of the ternary copper–indomethacin
complexes [Cu2(Indo)4L2] (IndoH=indomethacin= 1-(4-chlorobenzoyl)-5-methoxy-2methyl-1H-indole-3-acetic acid; L=acetonitrile (AN), N,N-dimethylacetamide (DMA),
tetrahydrofuran (THF), or pyridine (Py)) are reported [23]. All four complexes contain a
dinuclear ‘Cu-acetate’ molecular structure in which the carboxyl groups of the
indomethacin ligands act as bridges (Fig. 4-15). The Cu-Cu distances of 2.649(3),
2.6240(8), and 2.6784(8) Ao ; Cu-(Ac) distances of 1.964, 1.970, and 1.967 Ao ; and CuL distances of 2.132(6), 2.1805(17), and 2.177(2) Ao , respectively, for L=DMA, THF
and Py, are typical of such distances in dinuclear complexes of this type. There are two
independent complexes in the AN adduct with Cu-Cu distances of 2.6311(11) and
2.6206(8) Ao; Cu-O(Ac) distances of 1.965 and 1.965 Ao ; and Cu-Lav distances of
2.184 and 2.197 Ao , respectively. The pyridine complex exists mainly as a monomer in
solution, which may be associated with the longer Cu-Cu bond in this adduct as
compared to the other complexes.
77
Fig. 4-15: Structure of [Cu2(Indo)4L2].
The interaction between indomethacin anions and heavy metal ions, such as
cadmium, zinc and copper(II) ions, was studied in aqueous solution by polarographic
techniques [24]. Indomethacin anions form complexes with these heavy metal ions: the
complex formed with cadmium ions is sparingly soluble, while more soluble and also
stronger complexes are formed with zinc and copper(II). At high concentrations, where
indomethacin anions undergo self-aggregation, these last compounds are solubilised.
This property is briefly discussed and compared to that of bile salts. In the presence of
calcium ions, indomethacin forms a poorly soluble salt and no evidence was detected
for the formation of complex species. The zinc complex of indomethacin has been
synthesised by a modified method [25], characterised and has been found to possess a
ligand-metal ratio of 2:1. In spite of a very small content of zinc present in it as
compared to zinc-aspirin, zinc-indomethacin is 3-times more potent than the parent drug
which may be mainly due to an appreciable increase in its solubility and dissolution
rate. Its ulcerogenic effects are negligible when administered at 1.5-times its own ED50.
This indicates that the dose of indomethacin and hence its ulcerogenic effects may be
reduced significantly by complexing it with zinc, without affecting its therapeutic
action. Some studies were intended to compare the effects of aspirin, 3,5diisopropysalicylic acid (3,5-DIPS), and indomethacin with those of their copper
complexes: Cu(II)iaspirinate)4, Cu(II)z(3,5- DIPS)4, and Cu(II)2(indomethacinate)4 as
well as Cu(II)2(acetate)4 on polymorphonuclear leukocyte (PMNL) random and
directional migration, in addition to their anti-inflammatory activities [26]. Experiments
were performed both in vivo and in vitro. In vitro modifications of PMNL migration
were measured with the Boyden chamber using N-formyl-methionyl-IeucylInternational Science Congress Association
78
phenylalanine (fMLP) as the chemoattractant and in the agarose assay using fMLP and
serum chemotactic derivatives of complement as chemoattractants. In vivo antiinflammatory activities of these compounds were determined after induction of a
seruminduced pleurisy in the rat, and measurement of exudate volume and number of
exudative cells 4 hr later. Copper complexes of non-steroidal anti-inflammatory drugs
(NSAIDs) were found to be more effective in decreasing random migration and
chemotaxis of PMNLs than their parent drugs or Cu(II)2(acetate)4 in in vitro studies.
Only chemotaxis was found to be reduced significantly for PMNLs obtained from
pleuritic rats after in vivo treatment and the order of copper complex effectiveness was:
Cu(lIh(indomethacinate)4 > Cu(II)z(3,5-DIPS)4 > Cu(lI)z(aspirinate)4 All doses of
Cu(II)(acetate)4 administered in vivo failed to affect chemotactic activity. Copper
complexes of NSAIDs were also more effective than their parent drugs as antiinflammatory agents, and Cu(II)z(acetate)4 had no anti-inflammatory activity in this
model of inflammation, The order of anti-inflammatory activity was:
Cu(II)(indomethacinate)4 > Cu(II)(3,5-DIPS)4 >Cu(II)(aspirinate)4.
REFERENCES
1- disease-modifying antirheumatic drug at Dorland's Medical Dictionary "Disease
modifying antirheumatic drugs (DMARDs)". http://www.uptodate.com/patients
/content/topic.do?topicKey=arth_rhe/5016.
2- http://www.novartis.com/about-novartis/company-history/index.shtml.
3- http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1434053
4- Salmann, AR (1986) The history of diclofenac. Am. J. Med. 80(4B):29-33.
5- "Data Sheet: Voltaren Rapid 25". Information for Health Professionals. Medsafe New Zealand Medicines and Medical Devices Safety Authority. 2007-07-10.
http://www.medsafe.govt.nz/profs/datasheet/v/voltarenrapidtab.htm.Retrieved 200903-17.
6- Dutta NK, Annadurai S, Mazumdar K, Dastidar SG, Kristiansen JE, Molnar J,
Martins M, Amaral L (2000). "The anti-bacterial action of diclofenac shown by
inhibition of DNA synthesis". Int. J. Antimicrob. Agents 14 (3): 249–51.
doi:10.1016/S0924-8579(99)00159-4. PMID 10773497.
7- Hart F, Boardman P (October 1963). "Indomethacin: A new non-steroid antiinflammatory agent". Br Med J 5363 (5363): 965–70. doi:10.1136/bmj.2.5363.965.
PMID 14056924.
8- Ferreira S, Moncada S, Vane J (Jun 23 1971). "Indomethacin and aspirin abolish
prostaglandin release from the spleen". Nat New Biol 231 (25): 237–9.
doi:10.1038/231237a0. PMID 5284362.
9- Giles W, Bisits A (October 2007). "Preterm labour. The present and future of
tocolysis". Best Pract Res Clin Obstet Gynaecol 21 (5): 857–68.
doi:10.1016/j.bpobgyn.2007.03.011. PMID 17459777.
79
10- Angela Theodorou1, Mavroudis A. Demertzis1, Dimitra Kovala-Demertzi1,
Efthimia E. Lioliou2, Anastasia A. Pantazaki2 & Dimitrios A. Kyriakidis,
BioMetals 12: 167–172, 1999.
11- RAJ PAL SHARMA, RAJNI SHARMA, RITU BALA and PALOTH
VENUGOPALAN, Journal of Coordination Chemistry Vol. 58, No. 10, 2005, 899–
908.
12- Rajni Sharma , Raj Pal Sharma, Ritu Bala , B.M. Kariuki, journal of Molecular
Structure 826 (2007) 177–184.
13- Carlo Castellari, Giorgio Feroci , Stefano Ottani, Acta Cryst. (1999). C55, 907-910.
14- Ihsan M. Kenawi, Barsoum N. Barsoum, Maha A. Youssef, European Journal of
Pharmaceutical Sciences 26 (2005) 341–348.
15- Renzo Cini, Comments Inorg. Chem.. (2000),22, No 3-4,pp 151-186.
16- Dimitra Kovala-Demertzi, Sotiris K. Hadjikakou , Mavroudis A. Demertzis ,Yiannis
Deligiannakis, Journal of Inorganic Biochemistry 69 (1998) 223-229.
17- Dimitra Kovala-Demertzi, Journal of Inorganic Biochemistry 79 (2000) 153–157.
18- Dimitra Kovala-Demertzi, Angela Theodorou, Mavroudis A. Demertzis, Catherine
P. Rilptopoulou, Aris Terzis, Journal of Inorganic Biochemistry 65,151-157 (1997).
19- Geise Ribeiro , Marcel Benadiba, Alison Colquhoun, Denise de Oliveira Silva,
Polyhedron 27 (2008) 1131–1137.
20- Barbara Morzyk-Ociepa , Ewa Rozycka-Sokolowska, Journal of Molecular
Structure 784 (2006) 69–77.
21- Angeliki Galani, Dimitra Kovala-Demertzi, Nikolaos Kourkoumelis, Aglaia
Koutsodimou, Vaso Dokorou, Zbigniew Ciunik, Umberto Russo, Mavroudis A.
Demertzis, Polyhedron 23 (2004) 2021–2030.
22- Tomoyuki Watanabe, Naoki Wakiyama, Akira Kusai, Mamoru Senna, Powder
Technology 141 (2004) 227– 232.
23- Ying R. Morgan, Peter Turner , Brendan J. Kennedy, Trevor W. Hambley ,Peter A.
Lay, J. Ray Biffin, Hubert L. Regtop , Barry Warwick, Inorganica Chimica Acta 324
(2001) 150–161.
24- Adamo Fini, Giorgio Feroci, Giuseppe Fazio, European Journal of Pharmaceutical
Sciences 13 (2001) 213–217.
25- Olga Bruno, silvia schenone, Angilio Ranisa,Elisabetta Baraoceli, BioInorganic &
medicinal Chemistry 19 (2001) 629-636.
26- Monique roch-arveiller, Dien pham huy, Louis maman, jean-paul giroud, John r, J.
Sorenson, Biochemical Pharmacology, Vol. 39, No, 3. pp, 569-574. 1990.
80
CHAPTER 5
5-1- Antihistaminic drugs (Histamine
(
antagonist)
A histamine antagonist:
antagonist is an agent that serves to inhibit the release or action of
histamine.. Antihistamine can be used to describe any histamine antagonist, but it is
usually reserved for the classical antihistamines that act upon the H1 histamine receptor.
receptor
Antihistamines are used as treatment for allergies.. Allergies are caused by an excessive
response of the body to allergens, such as the pollen released by grasses and trees. An
allergic reaction indicates an excessive release, by the body, of histamines. Other uses
of antihistamines are to help
help with normal symptoms of insect stings even if there is no
allergic reaction.
structure
Fig. 5-1: Fexofenadine structure.
Fexofenadine Fig. 5-1,
5
(Allegra, Telfast, Fastofen, and Tilfur)
Tilfur is an
antihistamine drug used in the treatment of hayfever and similar allergy symptoms. It
was developed as a successor of an alternative to terfenadine (brand names include
inclu
Triludan and Seldane), an antihistamine with potentially serious contraindications.
Fexofenadine, like other second and third-generation
third
antihistamines does not readily
antihistamines,
cross the blood-brain
brain barrier,
barrier, and so causes less drowsiness than first-generation
first
histamine-receptor
receptor antagonists.
antag
It works by being an antagonist to the H1 receptor [1]. It
has been described as both second-generation
second
[2] and third-generation
generation [3]. The older
antihistaminic agent terfenadine was found to metabolize into the related carboxylic
acid,, fexofenadine. Fexofenadine was found to retain all of the biological activity of its
parent while giving fewer adverse reactions in patients, so terfenadine was replaced in
the market by its metabolite.
metabolite. Fexofenadine was originally synthesized in 1993 by
Massachusetts-based biotechnology company Sepracor,, which then sold the
development rights to Hoechst Marion Roussel (now part of Sanofi-Aventis),
Sanofi
and was
later approved by the Food and Drug Administration (FDA) in 1996. AMRI holds the
patents to the intermediates and production of fexofenadine HCl along with Roussel.
AMRI received royalty payments from Aventis that enabled the growth of AMRI.
Fexofenadine is indicated for the relief from physical symptoms associated with
seasonal allergic rhinitis and treatment of chronic idiopathic urticaria.
urticaria It is not a
therapeutic drug and does not cure but rather prevents the aggravation of rhinitis and
urticaria and reduces the severity of the symptoms providing much relief from repeated
sneezing, runny nose, itchy eyes and general body fatigue caused by rhinitis and
81
urticaria.
rticaria. It is a safe and easy to use drug available in doses as indicated below. Also
unfortunately, to our knowledge, few papers report protonation constants for this ligand
[4-6],, in evident contrast with the number of studies dealing with carbocysteine metal
complexes in aqueous solution. A mucolytic agent or expectorant is any agent which
dissolves thick mucus and is usually
usually used to help relieve respiratory difficulties. It does
so by hydrolyzing glycosaminoglycans, tending to break down/lower the viscosity of
mucin-containing
containing body secretions/components. The viscosity of mucous secretions in
the lungs is dependent upon the concentrations of mucoprotein, the presence of disulfide
bonds between these macromolecules and DNA.. An expectorant (from the Latin
expectorare,
torare, to expel from the chest) is a medication that helps bring up mucus and
other material from the lungs, bronchi, and trachea.. An example of an expectorant is
guaifenesin which promotes drainage of mucus from the lungs by thinning the mucus
and lubricating the irritated respiratory tract.
tract. Sometimes the term "expectorant" is
incorrectly extended to any cough medicine. An expectorant increases bronchial
secretions and mucolytics help loosen thick bronchial secretions. Expectorants reduce
the thickness or viscosity of bronchial secretions thus increasing mucus flow that can be
removed more easily through coughing; Mucolytics break down the chemical structure
of mucus molecules. The mucus becomes thinner and can be removed more easily
through coughing" [3].
Fig. 5-2: Carbocysteine structure.
Carbocisteine is a mucolytic that reduces the viscosity of sputum and so can be
used to help relieve the symptoms of Chronic Obstructive Pulmonary Disorder (COPD)
(
and bronchiectasis by allowing the sufferer to bring up sputum more easily. For these
indications, it is available under the trade name Mucodyne (Beacon
(Beacon Pharmaceuticals).
Pharmaceuticals
Other trade names include Solmux (Westmont
(
Unilab,, Philippines), Rhinathiol (Sanofi(
Aventis,, France), Humex (Urgo
(
Laboratories,, France), Fluditec (Innotech,
(
Latvia),
Exputex (Shire plc,, UK), Reodyn (Orion
(
Pharma,, Finland), Carbotoux 375 mg capsule
and paediatric suspension (PPN, Cambodia) and Carbolin (carbocisteine BP 375 mg,
SK+F, Bangladesh) [7]]. Carbocisteine should not be used with antitussives (cough
suppressants) or medicines that dry up bronchial secretions. The great importance that
S-carboxymethyl-l-cysteine
cysteine (carbocysteine, ccys) has in medicine and biology can be
immediately
ely appreciated by the several papers that can be found by simply keying one
of its numerous synonyms in some web search engines. In fact, this aminoacid
represents one of the most common drugs, mainly used as “mucolytic” agent. However,
new studies are continuously
ntinuously performed with the aim of discovering new properties and
82
functions: for example, carbocysteine inhibits virus infections and bacteria attachment
in human epithelial cells of respiratory apparatus [8, 9], it is used in the management of
herbicide poisoning [10], and, very important from an environmental point of view, it is
employed in soil remediation by complexometric extraction of metal contaminants
(mainly copper) [11], thanks to its ability to form quite stable complexes with several
metal cations [12–14]. Metal chelation by carbocysteine represents a very interesting
subject not only for environmental chemists, but for biochemists too, because this bioligand may modify bioavailability of some metals in vivo [13]. However, for a correct
evaluation of the binding ability of carbocysteine, in particular in natural waters and
biological fluids, an accurate knowledge of its acid–base behavior is needed.
REFERENCES
1- Dicpinigaitis PV, Gayle YE (November 2003). "Effect of the second-generation
antihistamine, fexofenadine, on cough reflex sensitivity and pulmonary function".
British journal of clinical pharmacology 56 (5): 501–4.
2- Vena GA, Cassano N, Filieri M, Filotico R, D'Argento V, Coviello C (2002).
"Fexofenadine in chronic idiopathic urticaria: a clinical and immunohistochemical
evaluation". International journal of immunopathology and pharmacology 15 (3):
217–224. PMID 12575922.
3- Adams, Holland, & Bostwick (2008). Pharmacology for Nurses: A Pathophysiologic
approach. Author. Upper Saddle River, New Jersey.
4- R. Nakon, E.M. Beadle and R.J. Angelici, J. Am. Chem. Soc. 96 (1974) (3), pp.
719–725.
5- V. Brumas, M. Venturini, M. Filella and G. Berthon, J. Inorg. Biochem. 37 (1989)
(4), pp. 309–323.
6- M. Cromer-Morin, J.P. Scharff, M. Claude and M.R. Paris, Anal. Chim. Acta 104
(1979) (2), pp. 299–306.
7- Clemente Bretti , Alba Giacalone , Antonio Gianguzza , Demetrio Milea, Silvio
Sammartano, Fluid Phase Equilibria 252 (2007) 119–129.
8- G. Cakan, M. Turkoz, T. Turan, K. Ahmed, T. Nagatake, Microb. Pathog.34 (6)
(2003) 261–265.
9- H. Yasuda, M. Yamaya, T. Sasaki, D. Inoue, K. Nakayama, M. Yamada, M. Asada,
M. Yoshida, T. Suzuki, H. Nishimura, H. Sasaki, Eur. Resp. J. 28 (2006) 51–58.
10- N. Lugo-Vallin, I. Maradei-Irastorza, C. Pascuzzo-Lima, M. Ramirez-Sanchez, C.
Montesinos, Vet. Hum. Toxicol. 45 (1) (2003) 45–46.
11- T. Xie, W.D. Marshall, J. Environ. Monit. 3 (2001) 411–416.
12- R. Nakon, E.M. Beadle, R.J. Angelici, J. Am. Chem. Soc. 96 (3) (1974) 719–725.
13- V. Brumas, M. Venturini, M. Filella, G. Berthon, J. Inorg. Biochem. 37 (4) (1989)
309–323.
14- M. Cromer-Morin, J.P. Scharff, M. Claude, M.R. Paris, Anal. Chim. Acta 104 (2)
(1979) 299–306.
83
CHAPTER 6
6-1- Folic acid
Folic acid, Folate: IUPAC: (2S)-2-[[4-[(2-amino-4-oxo-1H-pteridin-6yl)methylamino]benzoyl]amino]pentanedioic acid MW: 441.398 and MF: C19H19N7O6.
Folic acid is named after the Latin word, “folium” for leaf. Folic acid is structurally
composed of pteroic acid and glutamic acid connected via an amide linkage (Fig. 6-1).
Both of the carboxyl groups (a- and c-carboxyl) of the glutamate moiety are accessible
for a potential reaction with an amino-group of any functional ligand. Several studies in
recent years describe the derivatization of folic acid at the c-carboxyl group of the
glutamate moiety [1]. To date folate conjugates of chemotherapeutic agents [2, 3],
antisense oligonucleotides and ribozymes [4, 5] proteins and protein toxins [6, 7]
immuno therapeutic agents [8, 9] as well as liposomes with entrapped drugs [10, 11],
plasmids [12, 13] and radiopharmaceutical agents [14] have been synthesized and
successfully tested in cancer cells over expressing the folate receptor FR on their
surface. The FR is a high affinity membrane protein which is over expressed on a wide
variety of tumor cells, but highly restricted in normal tissues.
Fig. 6-1: Structure of folic acid.
Folic acid (folinic acid, folacin, pteroylglutamic acid) is essential for the synthesis
of adenine and thymine, two of the four nucleic acids that make up our genes, DNA and
chromosomes. It is also required for the proper metabolism of the essential amino acid
methionine that is found primarily in animal proteins. A folic acid deficiency has been
clearly linked to an elevated level of homocysteine, a sulfur-containing amino acid.
High homocysteine levels, in turn, have been linked to cardiovascular disease and a host
of other undesirable conditions. This vitamin was discovered by Dr. Lucy Wills, while
researching how to prevent anemia (loss of red blood cells) during pregnancy.
Synonyms for folic acid are vitamin B9, folacin, Pteroylglutamate,
Pteroylmonoglutamate, and folate [15].
Vora, et al., [16] study and identify the degradation products for folic acid which
may form under thermal stress. An attempt was made to identify each of the
decomposition products using various analytical techniques, such as infrared
spectroscopy, mass spectroscopy, and X-ray diffraction, which suggested that the
glutamic acid fragment of folic acid is lost first, as evidenced by acid loss and amide
84
enhancement in the IR spectra. The vitamin was ultimately degrading to carbon
fragments and further identification was not necessary. The chemistry of metalcarboxylates continues to be an area of intense research investigations in view of its
diverse applications, ranging from the relevance of metal-carboxylate complexes as
model systems for the metalloactive sites in bioinorganic chemistry [17, 18] to their
usefulness as novel materials in materials science. Metal oxides can be readily prepared
from metal-carboxylate precursors by thermal decomposition methods [19]. Metalcarboxylates exhibit fascinating structural features. The structural diversity encountered
in metal-carboxylate complexes can be attributed to the versatile ligational behavior of
the carboxylate group which can function like a bidentate ligand binding to a single
metal or alternatively as a bridging bidentate ligand coordinating to two metals or as a
monodentate ligand [20, 21]. The three different coordination modes were reported as
shown in Fig. 6-2 [22].
M
O
O
C
O
I
R
M
M
C
O
R
O
C
M
II
R
O
III
Fig. 6-2: Coordination modes of the carboxylate group.
i- When the carboxylate group coordinates the metal ion in a monodentate manner, the
difference between the wavenumbers of the asymmetric and symmetric carboxylate
stretching bands, Δν = νasCOO- - νsCOO-), is larger than that observed for ionic
compounds. ii- When the ligand chelates, Δν is considerably smaller than that for ionic
compounds, while on the asymmetric bidentate coordination, the values is in the range
characteristic of monodentate coordination [23]. iii- The characteristic wavenumber
difference, Δν, is larger than that for chelated ions and nearly the same as observed for
ionic compounds.
REFERENCES
1- Guo, W.J., Hinkle, G.H. and Lee, R.J., J. Nucl. Med., 40, 1563 (1999).
2- Ladino, C.A., Chari, R.V.J., Bourret, L.A., Kedersha, N.L. and Goldmacher, V.S.,
Int. J. Cancer, 73, 859 (1997).
3- Lee, J.W., Lu, J.Y., Low, P.S., Fuchs, P.L., Bioorg. Med. Chem., 10, 2397 (2002).
4- Matulic-Adamic, J., Sanseverino, M. and Beigelman, L., Tetrahedron Lett., 43, 4439
(2002).
5- Leamon, C.P., Cooper, S.R., Hardee, G.E., Bioconjugate Chem., 14, 738 (2003).
6- Leamon, C.P., Pastan, I. and Low, P.S., J. Biol. Chem., 268, 24847 (1993).
7- Ward, C.M., Acheson, N. and Seymour, L.W., J. Drug Target., 8, 119 (2000).
85
8- Kranz, D.M., Patrick, T.A., Brigle, K.E., Spinella, M.J., Roy, E.J., Proc. Natl. Acad.
Sci., USA 92, 9057 (1995).
9- Cho, B.K., Roy, E.J., Patrick, T.A. and Kranz, D.M., Bioconjugate Chem., 8, 338
(1997).
10- Gabizon, H.A.T., Goren, D., Tzemach, D., Mandelbaum, S.F., Qazen, M.M. and
Zalipsky, S., Bioconjugate Chem., 10, 289 (1999).
11- Shi, G.F., Guo, W.J., Stephenson, S.M. and Lee R.J., J. Control. Release, 80, 309
(2002).
12- Reddy, J.A. and Low, P.S., J. Control. Release, 64, 27 (2000).
13- Hofland, H.E.J., Masson, C., Iginla, S., Osetinsky, I., Reddy, J.A., Leamon, C.P.,
Scherman, D., Bessodes, M. and Wils P., Mol. Ther., 5, 739 (2002).
14- Mathias, C.J., Hubers, D., Low, P.S. and Green, M.A., Bioconjugate Chem., 11, 253
(2000).
15- McCollum, E.V.A., “History of Nutrition”, Boston: Houghton Mifflin (1957).
16- Vora, A., Riga, A. and Alexander, K., Instrumentation-Science-and-Technology,
30(2), 193 (2002).
17- Wendlandt, W.W., “Thermal Methods of Analysis”, Wiley, New York, (1974).
18- Pecoraro, V.L., Baldwin, M.J. and Gelasco, A., Chem. Rev., 94, 807 (1994).
19- Rane, K.S. and Verenkar, V.M.S., Bull. Mater. Sci., 24, 39 (2001).
20- Mehrotra, R.C. and Bohra, R., “Metal Carboxylates”, Academic Press, London,
(1983).
21- Mehrotra, R.C. and Singh, A., Prog. Inorg. Chem., 46, 239 (1997).
22- Deacon, G.B. and Phillips, R.J., Coord. Chem. Rev., 33, 227 (1980).
23- Alcock, N.W., Culver, J. and Roe S.M., J. Chem. Soc. Dalton Trans., 1447 (1992).
86
CHAPTER 7
7-1- Bleomycin and Streptonigrin metal complexes
Bleomycin (BLM) was originally isolated as a Cu2+ complex which has since been
extensively studied [1]. It has also been known to be an excellent ligand for binding
with several different metal ions [2], including Mn2+ [3, 4], Co2+/3+ [5], Ni2+/3+ [6], Cd2+
[7], and Ga3+ [8], ions. The d–d transitions of the Cu2+ complexes of BLM and
analogues are detected at ~ 600 nm with a molar absorptivity at around 110 M-1 cm-1.
The energy of the d–d absorption is higher than those of many Cu2+ centers in the range
of 650–750 nm, suggesting the presence of a strong ligand-field in a distorted 5- or 6coordination sphere [9]. The metal coordination became clear after the structure of a
Cu2+ complex of a biosynthetic intermediate of BLM was determined with
crystallography [10]. This intermediate contains all the metal-binding moieties, but
lacks the sugars and the peptidyl bithiazole moiety. In this complex, the Cu2+ is bound
to the ligand via imidazole, pyrimidine, the amines of aminoalamine, and the amide
nitrogen of hydroxyhistidine.
The diamagnetic Zn2+-BLM complex of BLM has been utilized as a structural
model for the paramagnetic Fe2+-BLM complex owing to the difficulty in highresolution NMR studies of the paramagnetic species. Previous 2D-NMR studies of ZnBLM strongly suggested that the metal is bound to BLM through the secondary amine
of aminoalanine, the amido-N and imidazole of hydroxy histidine, pyrimidine. This
coordination chemistry of Zn–BLM has been suggested to be similar to that of the
diamagnetic of Fe2+-BLM based on NMR studies [11,12]. However, this metal
coordination has recently been challenged by an NMR study of an analogous complex
Zn-tallysomycin [13], in which five N-containing donors are suggested, including the
primary amines of amino-Ala, pyrimidine, and the peptidyl amide and imidazole of
(OH) His with the pyrimidine at the apex and an SS chirality. This study also excludes
the binding of the carbamoyl group. Instead, the disaccharide covers the sixth binding
site. This disagreement in axial binding has also been raised in the study of HOO–Co3+
complexes of BLM and analogues discussed below.
Streptonigrin (SN) is known to bind different transition metal ions to function
properly [14, 15]. The interaction of metal-SN complexes with DNA has been proposed
on the basis of some optical studies [16, 17]. A redox active metal ion such as Fe(III)
and Cu(II) is required for this antibiotic to exhibit full antibiotic and antitumor activities
[18]. The redox-active Fe(III) and Cu(II) complexes have been shown to accelerate SNmediated DNA scission in the presence of NADH, thus enhance the anti-tumor activity
of this antibiotic [19]. These results indicate that metal ions are possibly directly
involved in the action of SN. However, the metal binding mode and structure of these
metal complexes could not be definitely determined
in these studies. Particularly, two different configurations of the drugs are possible for
metal binding (Fig. 7-1) with the metal bound through either the quinolinequinoneamine functionalities based on the crystal structure [20] or the quinolinequinonepicolinate functionalities that requires a significant twist of the crystal structure.
87
Fig. 7-1: Schematic structures of streptonigrin (SN). The structure A is metal-free drug
determined by means of crystallography, whereas the structure B represents the
configuration upon metal binding as determined by means of NMR relaxation. The
formation of structure B requires a dramatic twist of the C2–C2 bond in structure A.
Zn2+ binds SN to afford a few different complexes with different metal binding
modes at various temperatures, in which a 1:1 metal–drug complex is the predominant
complex [21]. A recent study of the crystal structure of a Zn2+ complex that mimics the
metal-binding moiety of SN showed the binding of the metal to the quinolinequinonepicolinate functionalities, corroborating the structures of several paramagnetic metal
complexes of the drug determined by means of NMR techniques discussed below. The
interaction of Zn2+-SN with DNA and oligonucleotides has been investigated with 1Hand 31P-NMR spectroscopy. This study concluded the requirement of metal ion for SN
binding to DNA [21] and revealed sequence preference in DNA binding of this
antibiotic, in which the binding of Zn2+-SN to d(GCATGC)2 shows noticeable spectral
changes whereas the complex does not affect the spectra of d(ATGCAT)2. SN can bind
several different paramagnetic metal ions, including Co2+, Fe2+, and Yb3+ ions, with
large formation constants to form 1:1 metal-SN complexes [22]. The paramagnetic Fe2+,
Co2+, and Yb3+ complexes of SN have been studied with 1H-NMR spectroscopy and
relaxation, and their structures have been determined [23]. The hyperfine-shifted 1HNMR signals of these paramagnetic complexes have been fully assigned. The protonmetal distances derived from the relaxation times of the hyperfine-shifted signals in
these complexes match those of the complex with the metal located at the
quinolinequinone-picolinate site (structure B, Fig. 10), but not the quinolinequinoneamine site based on the crystal structure (structure A). This configuration requires a
significant twist of the C2–C2 bond by 180° in the crystal structure of the drug.
REFERENCES
1- Umezawa, H., Maeda, K., Takeuchi, T. and Okami, Y., J. Antibiot., 19, 200 (1966).
2- Dabrowiak, J.C., “The coordination chemistry of bleomycin” J. Inorg. Biochem., 13,
317 (1980).
3- Burger, R.M., Freedman, J.H., Horwitz, S.B. and Peisach, J., Inorg. Chem., 23, 2215
(1984).
4- Ehrenfeld, G.M., Murugesan, N., Hecht, S.M., Inorg. Chem., 23, 1496 (1984).
5- Sugiura, Y., J. Am. Chem. Soc., 102, 5216 (1980).
88
6- Greenaway, F.T., Dabrowiak, J.C., Van Husen, M., Grulich, R. and Crooke, S.T.,
Biochem. Biophys Res. Commun., 85, 1407 (1978).
7- Otvos, J.D., Antholine, W.E., Wehrl, S. and Petering, D.H., Biochemistry, 35, 1458
(1996).
8- Papakyriakou, A., Mouzopoulou, B. and Katsaros, N., J. Inorg. Biochem., 86, 371
(2001).
9- Lever, A.B.P., “Inorganic Electronic Spectroscopy”, 4th Ed. Elsevier: London, 481
(1984).
10- Itaka,Y., Nakamura, H., Nakatani, T., Muraoka, Y., Fujii, A., Takita, T. and
Umezawa, H., J. Antibiot., 31, 1070 (1978).
11- Oppenheimer, N.J., Chang, C., Chang, L.H., Ehrenfeld, G., Rodriguez, L.O. and
Hecht, S.M., J. Biol. Chem., 257, 1606 (1982).
12- Akkerman, M.A.J., Neijman, E.W.J.F., Wijmenga, S.S., Hilbers, C.W. and Bermel
W., J Am. Chem. Soc., 112, 7462 (1990).
13- Calafat, A., Won, H. and Marzilli, L.G., J. Am. Chem. Soc., 119, 3656 (1997).
14- Hajdu, J., Metal Ions Biol. Syst., 19, 53 (1985).
15- Harding, M.M. and Long, G.V., Curr. Med. Chem., 4, 405 (1997).
16- White, J.R., Biochem. Biophys. Res. Commun., 77, 387 (1977).
17- Rao, K.V., J. Pharm. Sci., 68, 853 (1979).
18- Bolzan, A.D. and Bianchi, M.S., A review. Mutation Res, 488, 25 (2001).
19- Gutteridge, J., Biochem. Pharmacol., 33, 3059 (1984).
20- Chiu, Y. and Lipscomb, W.N., J. Am. Chem. Soc., 97, 2525 (1975).
21- Long, G.V., Harding, M.M., Fan, J.Y. and Denny, W.A., Anti-Cancer Drug Design,
12, 453 (1997).
22- Wei, X. and Ming, L-J., Inorg. Chem., 37, 2255 (1998).
23- Wei, X. and Ming, L-J., J. Chem. Soc. Dalton Trans, 2793 (1998).
89
CHAPTER 8
8-1- Different antibiotic metal complexes
Lanthanide(III) ions (Ln3+) have been very widely utilized as substitutes and
spectroscopic probes [1-3] for biological Ca2+ owing to their very similar ionic radii,
binding properties, and coordination chemistry, yet with much higher affinity constants
because of the higher charges of Ln3+ ions (thus is able to probe weak Ca2+ interactions)
[4-6]. Indeed, both Ln3+ and Ca2+ ions have been reported to bind anthracyclines (ACs),
in which Ln3+ ions show > 3 orders higher in affinity constants [7]. Early NMR studies
of the paramagnetic Yb3+-daunomycin complex did not yield useful information for the
description of the coordination chemistry of the complex because of the formation of a
mixture and the lack of full assignment of the paramagnetically shifted 1H-NMR
features [8]. The binding of several Ln3+ ions, including Pr3+, Eu3+, Dy3+, and Yb3+, with
ACs in both aqueous and methanol solutions under different conditions has recently
been revisited by means of electronic spectroscopy, cyclic voltammetry, and NMR
techniques.
The metal-binding capability of TCs has been well documented [9], including the
binding with alkaline earth and transition metal ions (VO2+, Cr3+,Mn2+, Fe2+/3+,
Co2+,Ni2+, Cu2+, and Zn2+) and Al3+ [10-12]. Tetracyclines (TCs) have been determined
to be present mainly as Ca2+-bound form (and Mg2+-bound form to a lesser extent) in
the plasma when they are not bound to proteins such as serum albumin. Thus, the bioavailability of TCs should be dependent upon the physical and biochemical properties of
their metal complexes instead of their metal-free forms.
Bacitracin requires a divalent metal ion such as Zn2+ for its antibiotic activity [13],
and can form a 1:1 complex with several divalent transition metal ions, including Co2+,
Ni2+, Cu2+, and Zn2+ [14-16]. The Co2+-bacitracin complex binds tightly to C55-isoprenyl
(undecaisoprenyl or bactoprenyl) pyrophosphate with a formation constant of 1.05×106
M-1. This binding capability of metallobacitracin presumably prevents the long-chain
pyrophosphate from dephosphorylation by a membrane-bound pyrophosphatase, which
subsequently inhibits cell wall synthesis because the hydrolytic product undecaisoprenyl
phosphate is required to covalently bind UDP-sugars for transport of the sugars during
cell wall synthesis. Thus, the binding of metal-bacitracin complexes to undecaisoprenyl
pyrophosphate is the key step in the inhibition of cell wall synthesis by this antibiotic
since the sugars become unavailable as building blocks during cell wall synthesis.
Although the formation of the Co2+-bacitracin-undecaisoprenyl pyrophosphate ternary
complex was suggested in previous studies, [17] the structure of different metalbacitracin complexes and the structure–activity relationship of this antibiotic were not
conclusively defined.
The ternary complex of Ni(II) with sulfasalazine as a primary ligand and alanine
(ala), aspartic acid (asp), histidene (hist), methionine (meth) and serine (ser) amino acids
as secondary ligands have been synthesized [18]. Characterization of the complexes was
based on elemental analyses, IR, UV-vis, mass spectra, magnetic moment and thermal
analysis (TG). The thermal stability of the complexes was studied and the weight losses
for the decomposition of the complexes were calculated and correlated with the mass
90
fragmentation pattern. In most cases, the amino acid moiety is removed along with the
Schiff base moiety leaving NiO as a metallic residue. The metallic residue was
confirmed by powder XRD measurements.
Cerium(IV), Thorium(IV) and Uranyl(II) complexes with the ammonium salt of
sulfasalazine drug have been studied [19]. The structures of the complexes were
elucidated using elemental analysis, IR and mass spectroscopy and thermal analysis.
The complexes were isolated in 1:1 and 1:2 (M:L) ratios. The molar conductance values
for Ce(IV), Th(IV) and UO2(II) chelates have been found to be 6.90, 10.20 and 7.18 Ω2
cm−1 mol−1, respectively. The relatively low values indicate the non-electrolytic nature
of these complexes [20]. This can be accounted for by the deprotonated carboxylic OH
group (used as ammonium salt) in all complexes and deprotonation of the
phenolicOHgroup in Ce(IV) and Th(IV) complexes. The neutrality of the UO2(II)
complexes has been interpreted by the deprotonated carboxylic group and the
coordination of the phenolic OH group to the metal without proton displacement. The
IR spectrum of H3Suz showed a medium broad band at 3439 cm−1 which attributed to
OH of the phenolic and carboxylic OH groups. The carboxylic OH group is not
considered in the spectra of complexes since ammonical solution of sulfasalazine was
used in which the carboxylic was used as the ammonium salt. The existence of water of
hydration and/or water of coordination in the spectra of the complexes render it difficult
to get conclusion from the phenolic OH group of the sulfasalazine, which would be
overlapped by those of the water molecules. The participation of the phenolic group is
further confirmed by clearifing the effect of chelation on the ν(C – O) stretching
vibration. The shift of the ν(C – O) of phenolic group, from 1281 cm−1 in the free H3Suz
[21] ligand to 1271–1256 cm−1 in the complexes indicated the participation of the
phenolic group in complex formation. Also the participation of the OH group is
apparent from the shift in position of the δ(OH) in-plane bending from 1394 cm−1 in the
free H3Suz ligand to 1388–1374 cm−1 in the complexes [22]. The presence of water
molecules in the above mentioned complexes is assisted by the appearance of a broad
band within the range 3450–3300 cm−1, which is attributed to ν(OH2) of the water
molecules associated with the complex formation. Also a bending vibration of the water
molecules; δ(OH2), is found in the range 965–914 cm−1. The other bending vibration of
the water molecules; δ(OH2), is usually around 1600 cm−1 which always interferes with
the skeleton vibration of the benzene ring (C=C vibration). The participation of the
carboxylic group in chelation can be indicated from the changes of the bands of the
asymmetric and symmetric stretching vibrations of the carboxylate group upon complex
formation. The spectrum of H3Suz ligand shows sharp bands at 1618 and 1427 cm−1
assigned for asymmetric and symmetric stretching vibrations of the carboxylate moiety,
respectively. These two bands are either slightly shifted to lower frequencies or
remained decreased markedly in intensity. This indicates that the carboxylate group
participated in complex formation with the metal ions [23]. Participation of the phenolic
and carboxylic OH groups is also confirmed by the appearance of new bands in the
complexes in the 472–439 cm−1 regions which may be assigned to the ν(M–O)
stretching vibration [21, 24]. Coordination of the nitrate anion to the Ce(IV) and Th(IV)
91
ions were also supported by the IR spectra of the nitrate complexes. The nitrato
complexes of Ce(IV) and Th(IV) ions displayed three strong bands due to the nitrate
group νasym.(NO2) at 1500 cm−1, νsym.(NO2) at 1270 cm−1 and ν(NO) at 987 cm−1
assigned to monodentate nitrate group.
Keeping in view the chemotherapeutic of the sulfa-drugs, Schiff base namely 2thiophene carboxaldehyde-sulfametrole (HL) and its tri-positive and di-positive metal
complexes have been synthesized and characterized [25] by elemental analyses, IR, 1HNMR, solid reflectance, magnetic moment, molar conductance, mass spectra, UV-vis
and thermal analysis (TGA and DrTG). The low molar conductance values suggest the
non-electrolytic nature of these complexes. IR spectra show that HL is coordinated to
the metal ions in a tetradentate manner through hetero five-membered ring-S and
azomethine-N, enolic sulfonamide-OH and thiadiazole-N, respectively. Zn(II), Cd(II)
and UO(II) complexes are found to be diamagnetic (as expected). The thermal behavior
of these chelates shows that the hydrated complexes loss water of hydration in first step
in case of uranium complexes followed loss coordinated water followed immediately by
decomposition of the anions and ligand molecules in the subsequent steps. The
activation thermodynamic parameters, such as ΔE, ΔH, ΔS and ΔG are calculated from
The DrTG curves using Coats Redfern method. The antimicrobial activity of the
obtained products was performed using Chloramphenicol and Grisofluvine as standards,
indicate that in some cases metallation increase activity than the ligand.
Chloramphenicol (Fig. 8-1) is also namely chloromycetine and Paraxin. It is a
bacteriostatic antimicrobial originally derived from the bacterium Streptomyces
venezuelae, isolated by David Gottlieb, and introduced into clinical practice in 1949. It
was the first antibiotic to be manufactured synthetically on a large scale.
Chloramphenicol is effective against a wide variety of microorganisms; it is still use of
chloramphenicol in eye drops or ointment for bacterial.
The important of metal interactions with antibiotics in relation to their subsequent
action is well recognized [26-29].
OH
1
O
OH
2
3
O-
NH
N+
O
Cl
Cl
Fig. 8-1: Structure of Chloramphenicol drug.
The CHL is a well known antibiotic, but its reactions with metals, in particular
with those of biological interest, were not much investigated. In the literature, there are
92
only a few papers concerning complexation of copper(II) by Chloramphenicol (H2L) but
with
rather
contradictory
results.
Medvedovskii
[30,31]
has
found
spectrophotometrically that the purple complex formed in the reaction of copper(II) with
CHL in alkaline aqueous solution (pH~13) is actually a complex anion with metal to
ligand ratio 1:2, and proposed [Na2(HL)2] complex formula. However, this purple
complex was unable to isolate in the solid state neither from aqueous nor butanol
solutions. Fazakerley [29] reinvestigated the same copper(II)/CHL system in both
aqueous and methanol solutions but could not reproduce the previous results. They have
isolated a green neutral complex from methanol solutions, which has the formula
Cu(C11H11N2O5Cl2)2.2H2O and expressed disbelief that alkaline metal can be
incorporated into complex. From aqueous solution these authors have obtained pale
green compound with the formula Cu(C9H11N2O4)2.2H2O which was obviously a
product of decomposition.
Quinolones are comprised of a large family of antibacterial agents such as
nalidixic acid, pefloxacin, norfloxacin, ofloxacin, and ciprofloxacin (Fig. 8-2) [32-36].
The first-generation nalidixic acid is active only against Gram-negative bacteria,
whereas the later generations, such as the fluoroquinolones with a fluorine atom on the
number 6 carbon (Fig. 7B), have been modified to become effective antibacterial agents
which exhibit a broad spectrum of activity highly against Gram-negative bacteria and
less active against Gram-positive bacteria and also show significant activity against
anaerobic bacteria. Fluoroquinolones have been further modified to produce
quinobenzoxazines (Fig. 7C), which are found to show anti-tumor activities (whereas
the parent quinolones lack such activities) believed to be attributable to their interaction
with topoisomerase II. Ciprofloxacin (Cipro1 of Bristol-Myers) is a prototypical
fluoroquinolone which has been brought on the stage in recent antibioterrorism
reactions.
Fig. 8-2: The structures of (A) nalidixic acid; (B) the prototypical fluoroquinolones (F
substitution at position 6) ciprofloxacin (Cipro); R1 = H; R2 = cyclopropyl, norflozacin;
R1= H; R2 = ethyl, andpefloxacin; R1 = CH3; R2 = ethyl; and (C) aprototypical
quinobenzoxazine.
The tetracyclines (TCs) have once been widely used as both external and internal
medicines for an extended period of time because of their broad-spectrum activity
toward both Gram-positive and -negative bacteria, and also their activity toward
93
rickettsiae, chlamydiae, and protozoans, such as the prototypical TC aureomycin (Fig.
8-3) produced by Streptomyces aureofaciens [37, 38]. The antibiotic activity of TCs is
attributed to their binding to the ribosome which inhibits protein synthesis. Their usage
has been limited in recent years because of side effects, including staining of teeth and
increase in bacterial resistance. However, recent studies of the mechanism for bacterial
resistance of this drug has afforded new insight into rational design of analogues and
searching for new analogues of this broad-spectrum antibiotic family, such as the novel
9-glycylamido derivatives the ‘‘glycylcyclines,’’ for defending bacterial infections [39,
40]. One of the glycylcyclines 9-t-butylglycylamido-minocycline (GAR-936,
tigilcycline) is currently under phase II clinical trials [41].
Fig. 8-3: Schematic structure of aureomycin (7-chlortetracycline). Substitute OH for 5H and H for 7-Cl affords terramycin (5-oxytetracycline).
Although most antibiotics do not need metal ions for their biological activities,
there are a number of antibiotics that require metal ions to function properly [42] such
as bleomycin (BLM), streptonigrin (SN), and bacitracin. The coordinated metal ions in
these antibiotics play an important role in maintaining proper structure and/or function
of these antibiotics. Removal of the metal ions from these antibiotics can cause changes
in structure and/or function of these antibiotics. Similar to the case of
‘‘metalloproteins,’’
these
antibiotics
are
dubbed
‘‘metalloantibiotics’’.
Metalloantibiotics can interact with several different kinds of biomolecules, including
DNA, RNA, proteins, receptors, and lipids, rendering their unique and specific
bioactivities. In addition to the microbial-originated metalloantibiotics, many
metalloantibiotic derivatives and metal complexes of synthetic ligands also show
antibacterial, antiviral, and antineoplastic activities.
Sulfasalazine (Fig. 8-4, H3Suz) is a sulfa drug, a derivative of Mesalazine (5aminosalicylic acid abbreviated as 5-ASA), used primarily as an anti-inflammatory
agent in the treatment of inflammatory bowel disease as well as for rheumatoid arthritis
[43-46].
94
COOH
O
N
OH
NH
S
O
N
N
Fig. 8-4: Sulfasalazine (H3Suz).
The crystal structure of sulfasalazine was analyzed [47] for imide tautomer in
monoclinic space group. The bond lengths of C5-N2 and S1-N2 were shorter than those
observed in triclinic amide form which indicated conjugation between pyridine ring side
chains. The bulk of molecule was planar which resulted in extensive electron
delocalization. The amide tautomer was characterized by repeating unit which consisted
of centrosymmetric dimer assembled through N-H...O hydrogen bonds between
pyridylamine and carboxylic acid. When dealing with the interaction between drugs and
metal ions in living systems, a particular interest has been given to the interaction of
metal ions with antibiotics. Antibiotics that interact with metal ions constitute a class of
drugs which has been widely used in medicine both towards human beings and animals.
In particular, the interaction between transition metals and β-lactamic antibiotics such as
cephalexin has been recently investigated by several physicochemical and spectroscopic
methods, and with detailed biological data [48, 49]. Many drugs possess modified
pharmacological and toxicological properties when administered in the form of metallic
complexes. Probably the most widely studied cation in this respect is Cu(II), since a
host of low-molecular-weight copper complexes have been proven beneficial against
several diseases such as tuberculosis, rheumatoid, gastric ulcers, and cancers.
Amoxicillin is semisynthetic antibiotic (present as amoxicillin trihydrate or amoxicillin
sodium). It is an analog of ampicillin, derived from the basic penicillin nucleus;
6‐aminopenicillanic acid [50-52]. The amoxicillin trihydrate molecular formula is
C16H19N3O5S·3H2O and the molecular weight is 419.45 g/mol. Chemically, amoxicillin
trihydrate is [(2S, 5R, 6R)-6-[(R)-2- amino-2-(4-hydroxyphenyl)acetamido]-3,3dimethyl-7 -oxo-4-thia-1- azabicyclo[3.2.0]heptane-2-carboxylic acid] trihydrate and
may be represented structurally as shown in Fig. 8-5. Amoxicillin is a member of
penicillin’s group which is a very important class of β-lactamic antibiotics used in therapy
because of its specific toxicity towards bacteria. It is a semi synthetic, orally absorbed, broad
spectrum antibiotic. It is now widely used in a standard eradication treatment of gastric H. pylori
infection combined with a second antibiotic and an acid suppressing agent [53 ,54].
95
Fig. 8-5: Structure of Amoxicillin (Amox) ligand.
ligand
From a coordination chemistry perspective it has been demonstrated that all the βlactamic antibiotics possess a number of potential donor sites and they are known to interact
effectively with several metal ions and organometallic moieties, originating complexes [55,
[ 56].
Atoms involved in coordination and the structure of these
these complexes depend on several factors
including reaction medium, pH, conformational equilibrium occurring in solution state and
nature of the side chain bonded at C of the β-lactamic ring. The ß-lactam
lactam antibiotics possess a
number of potential donor sites,
sites, which interact effectively with Lewis acidic metals [57,
[ 58].
The stereochemistry and geometries of such complexes are highly dependent on several factors
including the reaction medium, pH and nature of the side chain bonded to the phenyl of the ßlactam ring. The pharmacology, clinical efficiency, resistance with enzymes to ß-lactam
ß
antibiotics and coordination chemistry with amoxicillin has been reported [59
[ -61].
Amoxicillin trihydrate (ACT) and ampicillin trihydrate (APT) have been coordinated
coordina to
copper salts in a 1:1 molar ratio in the presence of biuret reagent to form mixed ligand copper
complexes [62],
], which were further used for the treatment of the infections caused by most of
the Gram positive and Gram negative bacteria [63].
[
Their protein synthesis-inhibiting
synthesis
properties
[64]] due to their acidic nature were also reported [65].
[ ]. The basic nucleus of the antibiotics is 66
amino penicillanic acid, which consists of a thiolidine ring linked to a ß-lactam
ß lactam ring with a side
chain [66, 67]. Many
ny studies concerning the biochemical and pharmaceutical effects of
antibiotics when complexed with metal ions have been a subject of great interest for many
scientists. Amoxicillin antibiotic, known as 6-[D-α-(p-hydroxyphenyl)
6
hydroxyphenyl) acetamido] pencilanic
acid, has effect against urinary tract infection and used in the treatment of respiratory infections
and meningitis [68].
]. The metal complexation behavior of amoxicillin was studied extensively.
Lyle and Yassin [69]] studied the differential pulse polarographic behaviour
behaviour of nickel (II)
complex with amoxicillin at the dropping mercury electrode. Novel di and tri organotin (IV)
derivatives of amoxicillin of the type R2SnCl(Amox).2H2O, R2Sn(Amox)2.2H2O and
R3SnCl(AmoxH)Na.2H2O (R = Me. Bu and Ph) had been reported [70],
[
these studies
96
suggested that amoxicillin in the diorgano derivatives behaved as monoanionic (Amox =
deprotonated amoxicillin) bidentate ligand, coordinating the tin (IV) ion through the ester type
carboxylate and lactamic carbonyl. However in the triorgano derivative,
R3SnCl(AmoxH)Na.2H2O, the tin is coordinated only through the lactamic carbonyl that
acts as monodentate ligand. In both R2SnCl(Amox)2H2O and R3SnCl(AmoxH)Na.2H2O
trigonal bipyramidal configuration were proposed while in R2Sn(Amox)2.2H2O the
coordination geometry at Sn(IV) was skew-trapezoidal bipyramid, with two chelating
amoxicillin acted as bidentate ligand in the trapezoidal plane and the organic molecules in axial
positions. Novel triorganotin(IV) complexes of two β-lactamic antibiotics, 6-[d-(−)-β-amino-phydroxyphenyl-acetamido] penicillin (=amoxicillin) and 6-[d-(−)-α-aminobenzyl]penicillin
(=ampicillin), have been synthesized and investigated both in solid and solution states. These
complexes corresponded to the general formula R3Sn(IV)antib·H2O (R=Me, n-Bu, Ph;
antib=amox=amoxicillinate or amp=ampicillinate) [71]. Zayed and Abdullah prepared and
studied a series of complexes of different stoichiometric ratio of 1:1, 1:2 and 2:1, ( metal to
AmoxH) , and the proposed general formula was M(AmoxH)(H2O)w(H2O)x(OH)yClz (where M
= Fe(II), Co(III), w = 0, x = 2, y = 1, z = 1; M = Fe(III), w = 0, x = 1, y = 2, z =0; M = Ni(II),
Cu(II) and Zn(II) w = 2, x=0, y = 1, z = 0 ; where w = water of crystallization, x = coordinated
water, y = coordinated (OH-) and z = Cl- in the outer sphere of complex). In all complexes, the
coordination of the ligand to the metal ions was proved to be through the N of the amino group
and O of C=O of ß-lactum group.
Amoxicillin acted as monoanionic bidentate ligand coordinating the metal ion through
carboxylate as well as through the lactamic carbonyl group in its complexes with some
transition metal ions; Ag(I), Cu(II), Co(II), Zn(II) and Ni(II) [72]. To know whether the
amoxicillin act as ionic or in neutral manner on coordination, The synthesis and characterization
of heterobinuclear complexes of the general formula [MCl3(AmoxH)M`Cl2] (where M =
titanium (III), chromium (III) and iron (III); M` = zinc (II) and cadmium (II); AmoxH =
amoxicilline) were described [73] and amoxicillin exhibited penta-dentate manner. The three
sites along with the three chloride ions were used to form the most probable octahedral
geometry around the trivalent metal ions Ti(III), Cr(III) and Fe(III), while the other two sites
with the two other chloride ions were utilized to form the most probable tetrahedral arrangement
around the divalent metal ions Zn(II) and Cd(II). Complexes of Amoxicillin with with Bi(V)
were obtained in acidic media [74]. The new complexes of Amoxicillin with some transition
metal ions such as Ag(I), Cu(II), Co(II), Zn(lI) and Ni(II) showed an enhanced antibacterial
activity against several Escherichia coli, Staphylococcus aurous, Pseudonomous aerugionosa
compared to the simple antibiotic. Metal such as Co (II), Ni (II), Cu (II) and Bi (V) were
coordinated to a novel ligand which was made by coupling gentamicin and amoxicillin. These
were studied by various spectroscopic techniques which indicated a square planar arrangement
of ligand around the Co(II) ions [75]. Also, complexes of Co(II), Zn(II), Ni(II) and Mn(II) with
cinnemaldehyde, p-chlorobenzaldehyde and amoxicillin trihydrate were synthesis and
characterized [76]. The interaction of amoxicillin with Zn (II) ion has been found to form one
complex of 1:1 metal to ligand composition. The results showed that the complex formation
was affected by the nature of solvents, time, pH and temperature. The interaction of Al(III) with
amoxicillin (L) was studied by the pH-metric titration in aqueous solutions at 20°C and ionic
97
strength 0.1 (KNO3). In weakly acidic medium, complexes with the composition Al(OH)L and
Al(OH)2L were formed.
REFERENCES
1- Ming, L-J., “Paramagnetic lanthanide(III) ions as NMR probes for biomolecular
structure and function”, Dordrecht, Netherlands: NATO-ASI, Kluwer; (1995).
2- Nieboer, E., “The lanthanide ions as structural probes in biological and model
systems”, Struct. Bond, 22, 1 (1975).
3- Horrocks, W., Adv. Inorg. Biochem., 4, 201 (1982).
4- Bunzli, J-C.G. and Choppin, G.R., “Lanthanide probes in life, chemical, and earth
science”. Amsterdam: Elsevier (1989).
5- Evans, C.H., “Biochemistry of the Lanthanides”, New York, Plenum; (1990).
6- Williams, R.J.P., Struct. Bond, 50, 79 (1982).
7- Wei, X. and Ming, L-J., Inorg. Chem., 37, 2255 (1998).
8- Mclennan, I.J. and Lenkinski, R.E., J. Am. Chem. Soc., 106, 6905 (1984).
9- Martin, R.B., Met Ions Biol. Sys., 19, 19 (1985).
10- Mikulski, C.M., Fleming, J. and Fleming, D., Inorg. Chim. Acta, 144, 9 (1988).
11- Jezowska-Bojczuk, M., Lambs, L., Kozlowski, H. and Berthon, G., Inorg. Chem.,
32, 428 (1993).
12- Abd El-Wahed, M.G., Ayad, M. and El-Sheikh, R., Anal. Lett., 17, 413 (1984).
13- Storm, D.R. and Strominger, J.L., J. Biol. Chem., 249, 1823 (1974).
14- Scogin, D.A., Mosberg, H.I., Storm, D.R. and Gennis, R.B., A. Biochemistry, 19,
3342 (1980).
15- Seebauer, E.G., Duliba, E.P., Scogin, D.A., Gennis, R.B. and Belford, R.L., J. Am.
Chem. Soc., 105, 4926 (1983).
16- Mosberg, H.I., Scogin, D.A., Storm, D.R. and Gennis, R.B., Biochemistry, 19, 3353
(1980).
17- Stone, K.J. and Strominger, J.L., Proc. Nat. Acad. Sci., USA, 68, 3223 (1971).
18- Soliman, A.A, Spectrochim. Acta Part A, 65(5) 1180 (2006).
19- Mohamed, G.G, Soliman, A.A., El-Mawgood, M.A., J. Spectrochim. Acta Part A,
62(4-5), 1095 (2005).
20- Filo, J.J., Terron, A., Mulet, D. and Merno, V., Inorg. Chim. Acta, 138, 197 (1987).
21- Zayed, M.A., Nour El-Dien, F.A., Mohamed, G.G. and El-Gamel, N.E.A.,
Spectrochim. Acta Part A, 60, 2843 (2004).
22- Soliman, A. and Linert, W., Thermochim. Acta, 338, 67 (1999).
23- Sandhu, G.K. and Verma, S.P., Polyhedron, 6, 587 (1987).
24- Santi, E., Torre, M.H., Kremer, E., Etcheverry, S.B. and Baran E., Vib. Spectrosc.,
5, 285 (1993).
25- Carmen, M.S., Spectrochim. Acta Part A, 66(4-5), 1271 (2007).
26- Refat, M.S., Spectrochim. Acta Part A, 68(5), 1393 (2007).
27- Pellerito, F.T., pellerito, C., Fontana, A., Distetano, R., pellerito, L., Cambria, M.T.
and Mansueto, C., J. Inorg. Biochem., 72, 115 (1998).
98
28- Seremic, M., Antic A.–Jovanovic and Bojovic, V., Inorg. Nucl. Chem. Letters,
14,473 (1998).
29- Fazakerley, G.V., Linder, P.W. and Nassimbeni, L.R., Inorg. Nucl. Chem. Letters,
9, 1069 (1973).
30- Medvedovskii, A.O., Farm. Zh. (kiev), 23, 50 (1968).
31- Medvedovskii, A.O., Farm. Zh. (kiev), 25, 21 (1970).
32- Cornett, J.B. and Wentland, M.P., Ann. Rep. Med. Chem., 21, 139 (1986).
33- Chu, D.T., Med. Res. Rev., 19, 497 (1999).
34- Chu, D.T.W. and Fernandes, M.P., Antimicrob. Agents Chemother., 33, 131 (1989).
35- Wolfson, J.S. and Hooper, D.C., editors, “Quinolone antimicrobial agents”,
Washington, DC: American Society for Microbiology; (1993).
36- Andriole, V.T., “The quinolones”, 3rd edn. San Diego: Academic, (2000).
37- Kaji, A., Ryoji, M., “Tetracycline” In: Hahn FE, editor, Antibiotics. Berlin:
Springer; (1979).
38- Chopra, I., Hawkey, P.M. and Hinton, M., Antimicrob. Agents Chemother., 29, 245
(1992).
39- Testa, R.T., Petersen, P.J., Jacobus, N.V., Sum, P.E., Lee, V.J. and Tally, F.P.,
Antimicrob. Agen. Chemother., 37, 2270 (1993).
40- Sum, P.E., Lee, V.J., Testa, R.T., Hlavka, J.J., Ellestad, G.A., Bloom, J.D.,
Gluzman, Y. and Tally, F.P., J. Med. Chem., 37, 184 (1994).
41- Johnson, A.P., Curr. Opin. Anti-Infect. Invest. Drugs, 2, 164 (2000).
42- Li-June, M., Med. Res. Rev., 23(6), 697 (2003).
43- Sutherland, L., Roth, D. and Beck, P., et al., Cochrane Database Syst. Rev., (2000).
44- Hanauer, S.B., Sandborn, W.J. and Kornbluth, A., et al., Am. J. Gastroenterol, 100,
2478 (2005).
45- Bell, C.M. and Habal, F.M., Am. J. Gastroenterol, 92, 2201 (1997).
46- Diav-Citrin, O., Park, Y.H. and Veerasuntharam, G., et al., Gastroenterology, 114,
23 (1998).
47- Blake-Alexander, J., Lin-Xiang, Schroder-Martin, Wilson-Claire and Yuan-RongXin, J. Acta-crystallographica- section c, crystal structure – communications, 60(4),
226 (2004).
48- Anacona, J.R., Coord J. Chem., 54, 355 (2001).
49- Lozano, J. and Borras, J., Inorg. J. BioChem., 31, 187 (1987).
50- Michael IP. "The Chemistry of β-Lactams". Glasgow. UK: Chapman &Hall; 1992.
51- Zayed MA, Abdallah SM. Spectrochim Acta A Mol Biomol Spectrosc. 2005; 61:
2231-2238.
52- Boles MO, Girven RJ, Gane PAC. Acta Crystallogr. 1976; B34:461-466.
53- Vakil N. and Cutler A., Am. J. Gastroenterol, 94 (5), 1197-1199 (1999).
54- Buzas G.M. and Szekely E., Orv. Hetil , 140 (3), 121-124 (1999).
55- Castanheira, Mariana; Sader, Helio S.; Desphande, Lalitagauri M.; Fritsche, Thomas
R.; Jones, Ronald N, Antimicrobial Agents and Chemotherapy 52(2), (2008), 570573.
99
56- Subramanian, Sreedhar; Roberts, Carol L.; Hart, C. Anthony; Martin, Helen M.;
Edwards, Steve W.; Rhodes, Jonathan M.; Campbell, Barry J. Antimicrobial Agents
and Chemotherapy, 52(2) (2009)., 427-434.
57- M.J. Neal. Medical Pharmacology at a Glance, 2nd Ed, p. 78, Blackwell, Oxford
(1991).
58- M. Neuman. Vademecum Degli Antibiotici ed Agenti Chemioterapici Anti-Infettivi,
5th Ed. (in Italian), p. 133, Sigma-Tau, Rome (1994).
59- D.M. Campoli-Richards, R.N. Brogden. Drugs, 33, 577 (1987).
60- W.M. Cort, J.W. Scott, M. Araujo, W.J. Mergens, M.A. Cannalonga, M. Osadca, H.
Harley, D.R. Parrish, W.R. Pool. J. Am. Oil Chemists Soc., 52, 174 (1975).
61- L. Seunjae, M. Yoshiki,M. Masashi, O. Hiroshi, I. Kuniyo. J. Biochem., 139, 1007
(2006).
62- M.S. Bhatia, S.G. Kashedikar, S.C. Chaturvedi. Ind Drugs, 33, 213 (1996).
63- R.S. Satoskazr, S.D. Bhandarkar. Pharmacology and Pharmacother Apeutics Vol. II,
11th Ed., p. 549, Popular Prakashan, Bombay (1990).
64- H.P. Rang. Pharmacology, 3rd Ed., p. 691, Churchil Livinston Pub., London (1996).
65- M.M. Dalc. Pharmacology, 3rd Ed., p. 725, Churchil Livinston Pub., London
(1998).
66- P.C. Fleming, M. Goldner, D.G. Glass. Inhibition of aerobacter cephalosporin blactamase by penicillins. J. Bacteriol., 98, 394 (1969).
67- M. Baczkowicz, D. Wojtowicz, J.W. Anderegg, C.H. Schilling, P. Tomasik.
Carbohydr. Polym., 52, 263 (2003).
68- J. Delgado and W.A. Remers, “Textbook of Organic Medicinal and Pharmaceutical
Chemistry”, 9th ed., J. Lippincott Co., 1991, 244.
69- S.L. Lyle and S.S. Yassin, Analytica. Chim. Acta, 274(2), 225(1993).
70- L. Pellerito, F. Maggio, M. Consiglio, A. Pellerito, G.C. Stocco and S. Grimaudo,
Applied Organometallic Chemistry, 1995, 9(3), 227.
71- R Di Stefano, M Scopelliti, C Pellerito, T Fiore, R Vitturi, M.S Colomba, P
Gianguzza, G.C Stocco, M Consiglio, L Pellerito, Journal of Inorganic
Biochemistry, Volume 89, Issues 3–4, 28 April 2002, Pages 279-292.
72- M. Imran, J. Iqbal, T. Mehmood and S. Latif, J. Biological Sciences, 2006, 6(5),
946.
73- Khalaf I. Khallowa, Nuhad A. Al-Omari, Tikrit Journal of Pure Science Vol. 13
No.(1) 2008, 152 – 155.
74- Kumar and P. Mishra, Main Group Chemistry Vol. 7, No. 1, March 2008, 1 – 14.
75- Parashuram Mishra, Biocoordination, International Journal Of Pharmaceutical
Sciences Review And Research, Volume 3, Issue 2, July – August 2010; Article
028.
76- Sunil Joshi, Vatsala Pawar , And V.Uma, International Journal Of Pharma And Bio
Sciences, Vol 2,Issue 1,Jan-Mar (2011).
100
CHAPTER 9
9-1-Metal complexes of purines and their derivatives
Erich and Hänggi [1] study the thermal behaviour of metal compounds of the
naturally occurring oxopurines hypoxanthine, xanthine and uric acid and of the
synthetic pyrazolopyrimidines allopurinol and alloxanthine as well as of the thiopurine
6-mercaptopurine has been investigated, using thermogravimetric and X-ray
crystallographic techniques. The thermogravimetric data confirm the structural
characteristics of the metal complexes. The degradation of hydrated complexes occurs in
two steps with a dehydration reaction followed by complete decomposition to the
corresponding metal oxides. Anhydrous compounds arc decomposed in one step overall
reactions. The temperature range of dehydrations of the hydrated complexes strongly
depends on the binding mode of the water molecules. The reaction rate of the final
decompositions of these complexes seems to be influenced by the respective metal ions.
Copper and iron complexes show a sharp increase in the reaction rate in respect of the
complexes of cobalt and nickel, whereas zinc, cadmium and manganese compounds are
slowly decomposed over a wide temperature range.
The oxopurines hypoxanthine and xanthine are of biological importance, since
they are metabolic intermediate products of purine metabolism. Hypoxanthine (1,7dihydro-6H-purin-6-one), formed by degradation of nucleic acids, is oxidized by the
molybdenum-and iron-containing enzyme xanthine oxidase via xanthine to uric acid,
which subsequently is released from the active site of the enzyme [2]. Disturbances in
purine metabolism result in an increase of the uric acid level and in the deposition of
sodium hydrogenurate monohydrate crystals in joints. This disease, known as gout, is
clinically treated by the drug Allopurinol (pyrazolo[3,4-d]pyrimidin-6-one) (Fig. 9-1),
which is also a substrate for xanthine oxidase [3]. Alloxanthine (pyrazolo[3,4d]primidin-2,6-dione), the enzymatic oxidation product of the drug Allopurinol,
inactivates xanthine oxidase by irreversible coordination to the reduced form of the
molybdenum centre of the enzyme [4].
O
8 N
NH
6
7
1
5
9
N
H
2
4
N
3
Fig. 9-1: Structure of Allopurinol drug.
101
Therefore, the information of uric acid is inhibited, and patients receiving the drug
Allopurinol excrete much of their purines as hypoxanthine and xanthine. The metal coordination capability of Allopurinol lies in great measure both in the existence of several
electron donor atoms and their disposition in the framework. Many metal complexes
involving Allopurinol as an uncharged (neutral) ligand and metals, such as Zn(II),
Co(II), Ni(II), etc. have been reported in the literature [5,6]. Generally, a monodentate
metal co-ordination through the pyrazole nitrogen atom N(8) has been generally
observed (Fig. 9-2), whereas a monodentate N(9) co-ordination of neutral Alp has been
only reported for a rhodium carbonyl compound [7]. Under acidic conditions N(9) coordination of Allopurinolium cation has been observed and a copper complex, having a
chlorine-bridge polymeric chain structure, has been evidenced [8].
HO
O
O
NH
6
7
8 N
6
9
N
H
7
1
5
2
4
N
3
N(1)-H, N(9)-H
HN 8
N
2
4
N
3
N(1)-H, N(8)-H
8 N
1
5
1
5
9
N
7
NH
6
9
N
H
2
4
N
3
enolic, N(9)-H
Fig. 9-2: Tautomeric equilibrium of Alp compound.
Recently interest in the trend of metal drug complexes, has increased in order to achieve
an enhanced therapeutic effect in combination with decreased toxicity. It has been found
that platinum or palladium complexes of purine derivatives show enhanced activity with
respect to free ligand [9]. In addition, metal complexes of purine ring are of importance
in view of their function as repository, slow-release or long-acting prodrugs for purine.
However, information on Allopurinol and their metal(II) complexes on the alkaline
medium is very scanty.
The quantification of metal-chelating activity of caffeic acid and ferulic acids was
successfully performed [10] by using a potentiometric system with data-analysis
computer programs. The method was applied to two phenolic models, which have been
systematically reported as antioxidants. Although a chain-breaking mechanism was
proposed, several studies pointed out the possibility of complexation of transition metals
that can participate in single-electron reactions and mediate the formation of oxygenderived free radicals. Results have shown that the complexation properties of the two
phenolic acids towards the transition metals are quite different: the activity of caffeic
acid was found higher than that of ferulic acid. The data are important to get insight into
the mechanism of action of antioxidants, and, in this case, could partially explain the
efficacy of caffeic acid in the protection of LDL oxidative damage. In addition, the
analytical method developed could be applied to quantify the chelating activity of
important biological compounds, such as allopurinol, uric acid, cinnamic acids,
102
flavonoids, and anthocianins, and, in that way, could be a valuable tool to understand
the mechanisms underlying their protective effects.
REFERENCES
1- Erich, D. and Hänggi, G., Institute of Inorganic Chemistry, University of Zürich,
Winterthurerstrasse 190, CH-8057 Zürich Switzerland (1993).
2- Stiefel, E.J., Progr. Inorg. Chem., 22, 1 (1977).
3- Hille, R. and Massey, V., "Nucleic acid-metal interactions", in T.G. Spiro (Ed.),
"Metals ions in Biology", 7, Wiley, New York, 443 (1985).
4- Hawkes, T.R., George, G.N. and Bray, R.C., J. Biochem., 218, 961 (1984).
5- Hangi, G., Shamalle, H. and Dubler, E., Acta Cryst. C47, 1609 (1991).
6- Hangi, G., Shamalle, H. and Dubler, E., Inorg. Chem., 27, 3131 (1988).
7- Sheldrick, W.S. and Gunther, B., Inorg. Chim. Acta, 151, 237 (1988).
8- Sheldrick, W.S. and Bell, P., Naturforsch Z., Teil B 42, 195 (1987).
9- Kishner, S., Wei, Y.K., Francies, D. and Bergman, S.G., J. Med., 9 (1969).
10- Fernanda, B., Limo, J., Isabel, P., Salette, R. and Christophe, S. J., Helvetica
Chimica Acta, 86(9) 3081 (2003).
103
CHAPTER 10
10-1- Metformin hydrochloride complexes
Metformin hydrochloride (MF-HCl); (N,N-dimethyl-imido-dicarbonimidic diamide
hydrochloride) or 1,1-dimethylbiguanide, it contains two imino (–C=NH) groups and the three
amino groups (i.e. primary (–NH2), secondary (–NH) and tertiary (–N(CH3)2) as donating
centers (Fig. 10-1). Metformin is commonly prescribed agent for the treatment of type II
diabetes. It induces multiple beneficial effects such as weight loss, lipid reduction and lowering
blood glucose levels [1, 2]. It is an oral hypoglycemic agent, which enhances insulin sensitivity
and is not effective in the absence of insulin [3]. It lowers blood glucose level in non-insulindependent diabetes mellitus (NIDDM) patients by suppressing hepatic glucose output and
enhancing peripheral glucose uptake. The mechanism of action involves binding of the polar
biguanide hydrocarbon side-chain to membrane phospholipids, evoking a change in the
electrostatic surface potential [4]. Subsequently, various metabolic effects are elicited,
depending on the target cell, tissue, organ, species [5, 6], and metabolic regulation [7]. The
available data on the relationship of structure to hypoglycemic activity for Metformin has
extensively been studied [8, 9]. Metformin is incompletely absorbed and facile recovery is about
30 % of an oral dose [10]; the absorption is slower than the elimination. Oral bioavailability was
50–60 % of the dose [11]. The difference between absorbed and available drug may reflect
minor presynaptic clearance of the drug or binding to the intestinal wall [12]. Concomitant food
intake may slightly impair Metformin absorption [13]. Metformin, because of its chemical
structure, does not interact with the liver and has a short half-life [14]. Higher doses may be
associated with an increased incidence of gastrointestinal adverse effects [15]. Several clinical
studies worldwide are using Metformin as a monotherapy or as an add-on therapy with
chemotherapeutic drugs to determine prospectively its efficacy and safety in treating human
cancer [16]. Metformin may also cause vitamin B12 deficiency [17].
H
N
N
NH
NH2
NH
Fig. 10-1: Structure of Metformin (MF) ligand.
It has been reported that specific combination of the Metformin with anionic agents,
which results proton transfer compounds PTC’s, leads to a significant improvements of the
hyperglycemia in a diabetic patient suffering from non-insulin-diabetes [18, 19]. Preparation of
different N,N-dimethyl biguanidinium containing PTC’s, however, has been of interest to a
number of researches for their comparable biological activities in comparison to Metformin [18,
20, 21]. Only eight structures concerning 1,1-dimethylbiguanide are available in the current
version of the Cambridge Structure Database [22]. Five of them contain a monocation: chloride
[23], bromide [24], nitrate [25], [TlBr4]3- salt [26] and perchlorate, with the cation enclosed in a
large complex [27]. Other three salts contain dications: oxalate, sulfate and a [CuCl4]2- complex
104
[28]. With regard to metal Metformin complexes, attempts have been made to make such
complexes for the treatment of diabetes but, however, they were poorly soluble in water [29].
The reaction of a proton transfer compound L, (MetH)2(dipic), (dipicH2 = 2,6pyridinedicarboxylic acid and Met =Metformin , with PdCl2 in water results in the formation of
novel tetracoordinated Pd II complex [Pd(dipic)(Met)]·2H2O indicating the participation of both
dipic2- and Met as chelating ligands. This seems that there is a further promising development
of these complexes as insulin-mimic compounds [30].
Besides having chelating ability, the biguanide derivatives demonstrated so far a large
spectrum of biological activities such antimicrobial [31], glucose lowering agents, analgesic and
antimalarial [32] as well as antimetabolite for organisms that inhibit the metabolism of folic acid
[33]. Having in view these aspects, new complexes of the type [VOL2]·xH2O with biguanide
derivatives [1-phenylbiguanide and 1-(o-tolyl)biguanide] together with the known vanadyl
complex of N,N-dimethylbiguanide were synthesized and characterized by elemental analysis
as well as IR and UV–Vis spectroscopy [34]. Considering the low solubility in water of
complexes, developing proper drug delivery systems requires the thermal analysis amongst
others [35]. The use of Metformin has been shown to possibly decrease the rate of specific
cancers when used in the treatment of type II diabetes. [36–39].
Metformin is a moderately strong base and combines with many elements of the
transition series, especially copper(II), nickel(II), cobalt(II), and platinum(II) as
[PtCl(MF)(DMSO)]Cl, [PtCl4(MF)(DMSO)], [Co(MF.HCl)(Cl)2], [CuCl2(MF)2]
,[Cu(MF)2]Cl2.2H2O, [Ni(MF)2](Cl)(OH) and [Zn(MF.HCl)Cl3] [40-43]. The metal
complexes of Metformin ligand are usually cationic in nature, and their highly color chelate
varies with the nature of the metal ion and its oxidation state, as well as with the number of
ligands in the complex due to the presence of the two imine groups in cis position thus acting as
a chelating agent. Metal complexes preparation has been the focus because of enhanced
biological activities of the corresponding drug metal complexes. Complexes of
[Mn(MF)2(Cl)2].2H2O,
[Fe(MF)2(Cl)2]Cl.4H2O,
[Ni(MF.HCl)2(Cl)2].6H2O,
[Cu(MF.HCl)2(Cl)2],
[Zn(MF.HCl)2](NO3)2.6H2O,
[Cd2(MF.HCl)(Cl)4(H2O)],
[Mg(MF.HCl)2(Cl)2].6H2O, [Sr2(MF.HCl)(Cl)4 (H2O)], [Ba(MF.HCl)2(Cl)2].2H2O,
[Pt(MF)4], [Au(MF)3]Cl3, and [Pd(MF)2]Cl2 were synthesized and characterized from
Metformin drug as a diabetic agent [44]. It has been found that the bidentate ligand can
chelate to metals in a square-planar configuration through four N atoms of two ligands. Like the
synthesis of a red copper complex of a deprotonated form (an anionic ligand). Complexes of
Co(II), Ni(II), Cu(I1) and Zn(I1) with Metformin have been synthesized and characterized [45],
and the bonding of the metal(II) ion to Metformin can be formulated in Figs. 10-2, 10-3 and 104. Metformin as a bidentate ligand coordinates to the silicon atom in a neutral as well as a
deprotonated form to yield two different types of complexes [46].
105
N
Me2N
NH2
C
CH
HN
NH
Cu
HN
NH
CH
CH
H2N
NMe2
N
8H2O
Fig. 10-2: Structure of deprotonated form of Metformin.
NH
(H3C)2N
C
H2
N
N
C
M
HN
C
NH
N
NH2
C
N(CH3)2
HN
Fig. 10-3: Structure of Metformin complexes with Co(II), Ni(II), Cu(II) and Zn(II).
H2N
C
H
N
NMe2
H
N
C
N
H
SCN
C
N
N
H
H2N
C
Si
N
Me2N
NCS
NMe2
H
N
C
N
H
SCN
NH
N
H
Me2N
2+
C
Si
HN
C
NH2
H
N
NCS
(NCS-)2
C
NH2
Fig. 10-4: Metformin-Silicon complex.
The atomic superposition and electron delocalization molecular orbital (ASED-MO) theory was
used to calculate structures and relative stabilities of Metformin-metal complexes. The relative
106
stabilities and decomposition pathways were discussed in terms of bond order, binding energy
and the nature of charge on the central metal atom. The electronic transitions and their energy
gaps were also studied. The optimization of the structures shows that the most stable state is
distorted from planarity for Co" and Ni" complexes [47]. Because this compound contains a
biguanidium group, it can form complexes with many metal ions [48-51]. Recently, reported
[52] that N,N-dimethylbiguanide loses its ability to lower blood glucose levels when forming a
monodentate complex with Zn2+ ions, but retains this ability when forming bidentate complexes
with Cu2+ and Ni2+ ions. Complexes of Co(II), Ni(II) and Cu(II) were synthesized from Schiff
base 2-{[(2-aminophenyl)imino]methyl}phenol and Metformin. The authenticity of the
transition metal complexes were characterized by elemental analyses, conductance and
magnetic susceptibility measurements, as well as spectroscopic (IR, electronic) and thermal
studies. IR spectral studies revealed the existence of the ligands in the amine form in the solid
state. The magnetic and electronic spectral studies suggest an octahedral geometry for all the
complexes. The Metformin acts as a bidentate ligand and Schiff bases of o-phynelendiamine
and salicylaldehyde acts as a tridentate ligand. Antimicrobial screening of the Schiff base,
Metformin and transition metal complexes were determined against the bacteria Escherichia
coli and Bacillus megaterium [53]. The new complexes M(DMBG)2(ClO4)2 (M:Mn, Ni, Cu
and Zn; DMBG: N,N-dimethylbiguanide) exhibit specific anti-infective properties as
demonstrated the low MIC values, a large antimicrobial spectrum and also inhibit the
ability of Pseudomonas aeruginosa and Staphylococcus aureus strains to colonize the
inert surfaces. These complexes exhibit also a low cytotoxicity levels on HeLa cells
[54]. Complexes of 1,1-dimethylbiguanide, namely with Cu(II), Rh(III) [55], Ir(III)
[56], Os(II) and Os(III) [57], Tc(V) and Re(V) complexes [58] have been studied.
Metformin hydrochloride chemically, it is known as 2-(N, N-dimethylcarbamimidoyl)
guanidine with a molecular formula of C4 H11 N5. HCl. Metformin hydrochloride is freely
soluble in water and is practically insoluble in acetone, ether and chloroform [59]. The pKa of
Metformin is 2.8 and 11.51. The melting point is 222-226ºC. Spectrophotometric methods [60,
61] were developed for the accurate determination of the compound in pure form and in drug
formulations. Metal complexes of some therapeutically active compounds have been
synthesized and characterized through elemental analysis, electrical conductivity, IR and UV/
VIS spectroscopy and thermal analysis [62]. Metal complexes of copper and nickel have shown
significant increase in hypoglycemic activity when compared to pure Metformin drug [63].
Biguanide is a strong organic base of pKa΄ =12.8 and pKa˝ =3.1 at 25 °C [64], and readily
forms acidic salts, with HCl to produce Metformin hydrochloride. Biguanide exists in
diprotonated form (H2Bg2+) in strong acid solutions, monoprotonated forms (HBg+) in weak
acid solutions, and neutral (Bg) in strong alkali solution. The hypoglycemic effects of
Metformin complexes with Co (II) and Zn (II) were found to be more effective than the parent
drugs [65].
107
REFERENCES
1- Stepensky D, Friedman M, Srour W, Raz I, Hoffman A. J. Control Release ; 71:
107-15 (2001).
2- Physicians, Desk Reference, Inc.; Medical Economics Company: New Jersey
(USA); Vol. 57( 2003).
3- The Merck Index. Published on CD by Chapman & Hall CRC. Merck & Co Inc.
Whitehouse Station, NJ, USA. Monograph No. 6001.(1999).
4- Damico C. Nursing, Drug Handbook, 22nd ed, Springhouse Publishers; pp.779
(2002).
5- Bailey CJ. The anti-hyperglycemic action of metformin. In: Krans HMJ (ed).
Diabetes and Metformin: A research and clinical update, Royal Society of Medicine
International Congress and Symposium Series, No.79, Royal Society of Medicine;
London, pp. 17-26 (1985).
6- Hermann LS. Metformin: A review of its pharmacological properties and
therapeutic use. Diabete Metabolisme ; 5(3): 233-45(1979).
7- Hermann LS. Metabolic effect of metformin in relation to clinical effects and sideeffects. In: van der Kuy A, Hulst SGT (ed). Biguanide therapy today, Royal Society
of Medicine International Congress and Symposium Series, No.48, Academic Press,
Grune & Stratton; London. pp.17-48 (1981).
8- Lu LP, Zhang HM, Feng SS, Zhu ML. Acta Crystallogr C ; 60(10): o740o743(2004).
9- Dolzhenko AV, Kotegov VP, Godina AT, Syropiatov BI, Kolotova NV,
Koz'minykh VO. Eksp Klin Farmakol ; 66(3): 36-38 (2003).
10- Tucker GT, Casey C, Phillips PJ, Conner H, Ward JD, Woods HF. Br J Clin
Pharmacol ; 12(2): 235-46(1981).
11- Pentikainen PJ, Neovonen PJ, Pentilla A. Eur J Clin Pharm ; 16(3): 195-202(1979).
12- Sirtori CR, Franceschni G, Gallikienle M.Clin Pharm Therap; 24(6): 683-93 (1978).
13- Melander A, Wahlin-Boll E. Acta Endocrinilogica Suppl ; 105(262): 119-23(1984).
14- Vigneri R, Goldfine ID. Role of metformin in treatment of diabetes mellitus.
Diabetes Care ; 10(1): 118-22 (1987).
15- Klepser TB, Kelly MW. Metformin hydrochloride: An antihyperglycemic agent.
Am J Health-Sys Pharm ; 54: 893-903(1997).
16- Jorge Eduardo Duque, Juliana Velez, Ismael Samudio, Enoch Lai, Journal of
Experimental and Clinical Medicine, ;4(3):140-144 (2012).
17- Liu KW, Dai LK, Jean W. Metformin-related vitamin B12 deficiency. Age Ageing
;35:200-201(2006).
18- P. Timmins, W.J. Winter, S.H. Srivastava, A. Bretnall, G. Wei, G.L. Powers, PCT
Int. Appl. WO9929, 314 (1999).
19- Y. Bonhomme, Ph. Briet, PCT Int. Appl. WO9940, 904 (1999).
20- J. Hellmut, H. Guenter, W. Annedore, R. Irmgard, CA 81: 91079u, Ger. East.104,
782 (1974).
21- G. Moinet, D. Cravo, G. Botton, D. Mesangeau, L. Doare, M. Kergoat, FR 2,
796,551 (2001).
22- Allen, F. H. Acta Cryst. B58, 380–388(2002).
23- Hariharan, M., Rajan, S. S. & Srinivasan, R. Acta Cryst. C45, 911–913 (1989).
24- Lu, L., Zhang, H., Feng, S. & Zhu, M. Acta Cryst. E60, o640–o641(2004a).
25- Zhu, M., Lu, L. & Yang, P. Acta Cryst. E59, o586–o588(2003).
26- He, Z., Zhu, M. & Ma, G. Acta Cryst. E58, m647–m649(2002).
108
27- Huang, L., Xi, P., Xu, M., Liu, T. & Zeng, Z. Anal. Sci. X-Ray Struct. Anal.
Online, 24, x289–x290(2008).
28- Lemoine, P., Tomas, A., Viossat, B. & Dung, N.-H. Acta Cryst. C50, 1437–1439
(1994).
29- L.C.Y. Woo, V.G. Yuen, K.H. Thompson, J.H. Mcneill, C. Orvig, J. Inorg.
Biochem. 76 (1999) 251.
30- A.Moghimi , H.R. Khavassi, F. Dashtestani, D. Kordestani, A. Ekram Jafari, B.
Maddah, S.M. Moosavi, Journal of Molecular Structure 996 (2011) 38–41.
31- Bailey CJ, Turner RC. Metformin. N Engl J Med. ; 334: 574–9 (1996).
32- Pignard P. Ann Biol Clin. ; 20:325–33(1962).
33- Siest G, Roos F, Gabou JJ. Bull Soc Pharm Nancy. ; 58:29–38 (1963).
34- Rodica Olar , Andreea Dogaru , Dana Marinescu , Mihaela Badea, J Therm Anal
Calorim, 2012, doi: 10.1007/s10973-012-2274-x
35- Kanaze FI, Kokkalou E, Niopas I, Georgarakis M, Stergiou A, Bikiaris D. J Therm
Anal Calorim. ; 83:283–90 (2006).
36- Bowker SL, Majumdar SR, Veugelers P, Johnson JA, Increased cancer-related
mortality for patients with type 2 diabetes who use sulfonylureas or insulin.Diabetes
Care ;29:254–258 (2006).
37- Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. BMJ
;330:1304–5(2005).
38- Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JMM. New users
of metformin are at low risk of incident cancer. Diabetes Care ;32:1620–1625
(2009).
39- Bodmer M, Meier C, Krahenbuhl S, Jick SS, Meier CR. Longterm metformin use
was associated with decreased risk of breast cancer. Diabetes Care (2010) 33:1304–
1308.
40- Bentefrit F, Morgant G, Viossat B, Leonce S, Guilbaud N, Pierre A, Atassi G, Dung
NH. J Inorg Biochem (1997) 68(1): 53-59.
41- Viossat B, Tomas A, Nguyen-Huy D. L, Acta Crystallogr. ; C51:213–5(1995).
42- Lemoine P, Chiatdmi M, Bissery V, Tomas A, Viosssat B. Acta Crystallogr. ; C52
(6):1430–6 (1996).
43- Zhu M, Lu L, Yang P, Jin X. Acta Crystallogr.; E58:m217–9 (2002).
44- Foziah A. Al-Saif , Moamen S. Refat,.J Therm Anal Calorim, 2012, doi:
10.1007/s10973-012-2459-3.
45- S.M. Abu-El-Wafa, M. A. El-Ries and F. H. Ahmed, Inorganica Chimica Acta,
136(1987) 127-131.
46- Meenu Puri , Metformin and Biguanide Complexes of Isothiocyanatosilane, Journal
of Phosphorus, Sulfur, and Silicon, 187:9,1026–1031(2012).
47- M. Donia , M. K. Awad, Journal of Thermal Analysis, VoI. 44 (1995)1493-1498.
48- Ray, P. Chem. Rev. 61, 313-359(1961).
49- Zhu, M.-L., Lu, L.-P., Jin, X.-L. & Yang, P. (2002). Acta Cryst. C58, m158-m159.
50- Zhu, M.-L., Lu, L.-P., Yang, P. & Jin, X.-L. (2002b). Acta Cryst. E58, m272-m274.
51- Lu, L.-P., Yang, P., Qin, S.-D. & Zhu, M.-L. (2004). Acta Cryst. C60, m219-m220.
52- Zhu, M.-L., Lu, L.-P. & Yang, P. (2004). Acta Chim. Sin. 62, 783-788.
53- S. S. Sharma, j. V. Ramani, D. P. Dalwadi, J. J. Bhalodia, N. K. Patel, D. D. Patel,
R. K. Patel, E-Journal of Chemistry (2011) 8: 1, 361-367.
54- Rodica Olar , Mihaela Badea, Dana Marinescu, Mariana-Carmen Chifiriuc, Coralia
Bleotu, Maria Nicoleta Grecu, Emilia-Elena Iorgulescu, Veronica Lazar , European
Journal of Medicinal Chemistry 45 (2010) 3027-3034.
55- Spacu, P. & Gheorghiu, C. (1968). J. Less Common Met. 15, 331–339.
109
56- Gheorghiu, C. (1969). Z. Anorg. Allg. Chem. 365, 91–99.
57- Spacu, P. & Gheorghiu, C. (1969). J. Less Common Met. 18, 117–122.
58- Marchi, A., Marvelli, L., Cattabriga, M., Rossi, R., Neves, M., Bertolasi, V. &
Ferretti, V. (1999). J. Chem. Soc. Dalton Trans. pp. 1937–1944.
59- The Indian Pharmacopoeia, Vol. 1, Govt. of India,Delhi (1996).
60- Annapurna MM,.Nagoji KEV, Srinivasa Rao S, Patro SS. Asian J. Chem. (2002);
14, 1775-78.
61- Ashour S, Kabbani R. Analytical letters. ; 36(2): 361-370 (2003).
62- Patrinoiu G, Patron L, Carp O, Stanica N. J Therm Anal Calori. (2003); 72, 489-95.
63- Nalamolu Koteswara Rao, M.M. Annapurna, Research Papers, Jasa 3 , July (2007).
64- Elpern, B. Chemistry of the Biguanides, Annals of the New York Academy of
Sciences (1968) .148:3, 577-586.
65- Sandeep RN, Nirankar NM, Pratibha P, Ashok K, Pitre KS. Indian J Exp Biol ;
34:81-2(1996).
110
CHAPTER 11
11-2- Pyridoxine hydrochloride (Vitamin B6)
Pyridoxine (Fig. 11-1) is 2-methyl-3-hydroxy-4,5-bis(hydroxymethyl)pyridine and its
synonyms are Adermine and Vitamin B6. Structurally related compounds play a relevant role in
a large number of biological systems. Many reactions catalyzed by the coenzymes of the
pyridoxal group are known to take place in a rather hydrophobic environment inside the enzyme
active site [1]. Vitamins are components of parenteral nutrition (PN) used for attending the daily
requirements and supplying deficiencies in neonates and, in their majority, are instable [2-4].
The vitamins of B6 group (VB6) that contain a pyridine ring in structure, including pyridoxol
(PN), pyridoxal (PL), pyridoxamine (PM) and their phosphate derivatives, are important natural
compounds essential in diet needed as the co-factor in some VB6-dependent enzymes involved
in the metabolism and synthesis of amino acids and other related compounds for the
maintenance of body cells due to their vital roles in various biological processes [5-7].
CH2OH
HOH2C
OH
N
CH3
Fig. 11-1: Structure of Pyridoxine (PN) ligand.
Pyridoxine along with pyridoxal and pyridoxamine assist in balancing sodium and
potassium as well as promoting red blood cell production. It is linked to cancer immunity and
helps to fight the formation of homocysteine. Pyridoxine can help the balance of hormonal
changes in women and aid the immunity system. Lack of pyridoxine may cause anemia, nerve
damage, seizures, skin problems, and sores in the mouth [8]. Vitamin B6 exists in three forms;
pyridoxal, pyridoxine, and pyridoxamine and all forms can be converted to the active vitaminB6 coenzyme in the body. Pyridoxal phosphate (PLP) is the predominant biologically active
form. Vitamin B6 is not stable in heat or in alkaline medium, so cooking and food processing
reduce its content. Both coenzyme and free forms are absorbed in the small intestine and
transported to the liver, where they are phosphorylated and released into circulation, bound to
albumin for transport to tissues. Vitamin B6 is stored in the muscle and only excreted in urine
when intake is excessive [9]. Vitamin-B6 deficiency is common in alcoholics and elderly
persons who consume an inadequate diet. Individuals taking medication to treat Parkinson's
disease or tuberculosis may take extra vitamin B6 under physician supervision. A nerve disorder
of the wrist has also been treated with large daily doses of B6 [10]. Pyridoxine under
various pH conditions exhibits four interchangeable ionic forms, i.e. at pH < 5 occurs as
cationic, neutral form and dipolar ion at pH 6.8, and anionic at pH > 8 [11]. Fig. 11-2 shows the
equilibria and the referenced values of dissociation constants (pKa) between these species in
aqueous solution. Ultraviolet spectra and acid dissociation constants, [11-13] as well as nuclear
111
magnetic resonance studies [14-16] of Pyridoxine and pyridoxamine show that the loss of the
first proton corresponds to the 3-hydroxy proton. The second ionization results in the loss of the
pyridinium 'proton. The crystal structure of pyridoxine hydrochloride shows that both the
pyridine nitrogen and the phenolic oxygen are protonated, as expected [17].
CH2OH
HOH2C
4'
CH2OH
5'
HOH2C
OH
O
N
H
CH3
HOH2C
pKa2 = 9
pKa1= 5
N
H
CH3
Dipolar
Cationic
CH2OH
O
5 4 3
2
6
1
N
CH3
Anionic
CH2OH
HOH2C
OH
N
CH3
Neutral
Fig. 11-2: Dissociation equilibria for ionic species and tautomeric forms for Pyridoxine
in aqueous solution.
Synthesis and comprehensive investigation of metal complexes with vitamins are an
important direction in modern chemistry. The development of methods for synthesizing new
coordination compounds, as well as the knowledge of their physicochemical properties and
structure, makes it possible to obtain new medical and veterinary preparations. Investigation of
the coordination chemistry of B-group vitamins is of special interest [18]. Pyridoxine is a
biocatalyst of many enzymatic transformations of amino acids in the organism, and the rate of
these transformations significantly increases in the presence of various metal ions [19, 20]. It has
been shown that pyridoxine complexes are better assimilated as compared to the pyridoxine
itself, which makes them promising for application in medicine and veterinary science. An
enhancement of the biological properties of pyridoxine in the presence of metal salts is possibly
associated with the transformations occurring in the geometric and electronic structures of
vitamin molecules upon complex formation.
Studies of the binding of metal ions with vitamin B6 compounds in the absence of
amino acids are of particular interest. Since the vitamin B6 compounds exist in solution as
tautomers, chelation to the metal ion depends very much on the pH of the solution or the
predominant form of the tautomer present. The compounds of vitamin B6 may act either as
unidentate ligands and bind the metal ion through the pyridine nitrogen or as a bidentate ligand
and chelate the metal ion by the phenolate oxygen and the nitrogen or oxygen at the adjacent
group in the 4'-position. There is also the possibility of unidentate binding through the phenolate
oxygen. The complex equilibria of Mn(II), Ni(II) and Co(II) with pyridoxine and pyridoxal led
to the assumption that pyridoxine and pyridoxal make use of the meta-oxy atom in the
112
formation of the complexes [21]. The liganding site in pyridoxine seems to depend on the type
of solvent medium used; a 13C-NMR study has shown that coordination of the metal ions by
pyridoxine is through the phenolic oxygen and the oxygen at the adjacent group in the 4'position in aqueous solution. In water-dimethylsulfoxide mixture, the pyridine nitrogen
becomes a more effective donor and with increasing proportions of dimethylsulfoxide some
cations are coordinated by dimethylsulfoxide rather than pyridoxine [22]. Single crystal x-ray
structure and 13C-NMR solution (D2O) studies [23] of Cd(PN)Cl2 indicate that the pyridoxine
molecule is bidentate and chelated to the cation through the phenolic oxygen and the oxygen at
the adjacent hydroxymethyl group. The importance of metallic ions in some enzymatic
processes involving vitamin B6 derivatives as cofactors is well-established [24]. Metal
complexes of vitamin B6 have been reported [25] to inhibit the growth as well as the
biosynthesis of RNA, DNA, and protein of Escherichia coli B-766. Pyridoxine displays
different coordination sites with metal ions with different charges and hard/soft character.
Chelation through phenolate oxygen and adjacent hydroxymethyl groups is common for
pyridoxine metal complexes [26-29]. Other bonding modes of pyridoxine are (i) simple
coordination through the pyridine nitrogen. (ii) chelation plus bonding through the pyridine
nitrogen [30-32] and (iii) chelation plus bridging through the coordinated phenolate or hydroxyl
group [33, 34]. Though considerable attention has been devoted to the study of vitamin B6
components [35-37], little attention has been paid to pyridoxine containing ternary complexes.
The coordination environment of pyridoxine in presence of imidazole containing ligand (s)
around the metal ion (Ni(II), Cu(II), and Zn(II)) and their biological activities have been studied
[38]. Deprotonation of pyridoxine to form the monoanionic species (PN H) − occurs in water at
microscopic pKa values of 8.35 for non-dipolar PN and 8.98 for dipole PN [39].
Dideprotonation (PN 2H) 2− also occurs giving dianion. In (PN 2H) 2−, the remaining proton is
borne by O3, while (PN H) −, in the solid state, the additional remaining proton is usually not
found on O2, but on the N atom (Fig. 11-3).
Fig. 11-3: Structure of the cation in [Cu(PN H)(PN)]NO3·2.5H2O
Several of the structurally characterized complexes of (PN H)− ([(VO2)2(PN H)2] [40],
[FeCl2(PN H)(H2O)] [41], [SnMe2(PN H)(H2O)]Cl·H2O [42] and [SnEt2(PN H)]Cl [131] exist
in the solid state as dimers in which the CH2O− group of the N-protonated form of the ligand
bridges between two metal centers. In [SnMe2(PN H)]NO3·2H2O, which was prepared by
113
reacting PN·HCl and SnMe2Cl2 in ethanol–water, neutralizing the reaction mixture, and
eliminating the chloride ions with AgNO3 [42], similar dimers are linked in polymeric chains.
The distorted octahedral coordination polyhedron of each tin atom is completed by an O3 atom
of a neighboring dimer to form Sn2O4C8 rings. In this compound the planar Sn2O2 ring formed
by the Sn and bridging O atoms makes an angle of 14° with the pyridine rings, which are totally
flat. Mononuclear complexes in which (PN H) − chelates through its deprotonated O1 and O2
atoms occur when the usual M–O2 bridging interaction is prevented by the presence of other
ligands that exhaust the normal coordination capacity of the metal. Thus in [Co(PN
H)(bipy)2](ClO4)2 [43], cobalt(III) has an octahedral coordination polyhedron defined by the
nitrogen atoms of the two bipy ligands and by the O1 and O2 atoms of (PN H)−, which chelates
but cannot bridge between metal atoms (Fig. 11-4). Similarly, in [MoO2(PN H)2]·3H2O [44],
the molybdenum is bound octahedrally to the two oxygen atoms and to the O1 and O2 atoms of
two (PN H)− ligands. The few known complexes of dideprotonated PN are all SnR22+
derivatives, namely [SnMe2(PN 2H)(H2O)]·0.5H2O, [SnEt2(PN 2H)]·CH3OH, [SnEt2(PN
2H)(DMSO)] and [SnBu2(PN 2H)] [146].
Fig. 11-4: Structure of the cation in [Co(PN H)(bipy)2](ClO4)2
REFERENCES
1. M.C. Ramusino, M. Bartolomei, L. Rufini, J. Inclusion Phenomena and Molecular
Recognition in Chemistry, 25 (1996) 113.
2. D. Ivanovic, A. Popovie, D. Radulovie, M. Medenica, J. Pharm. Biomed. Anal., 18
(1999) 999.
3. U. Holler, C. Brodhag, A. Knobel, P. Hofmann, V. Spitzer, J. Pharm. Biomed.
Anal., 31(2003) 151.
4. C. Aniceto, L.S. Canaes, O.F. Fatibello, C.C.S. Cavalheiro, Quim Nova, 23(5)
(2000) 637.
5. J.M. Sanchez-Ruiz, M. Martinez-Carrion, Biochemistry 25 (1986) 2915.
6. R.A. John, Biochim. Biophys. Acta 1248 (1995) 81.
114
7. S. Cinta, C. Morari, E. Vogel, D. Maniu, M. Aluas, T. Iliescu, O. Cozar, W. Kiefer,
Vib. Spectrosc. 19 (1999) 329.
8. Somer, M.A. and Elizabeth, R.D.(1999). Food & Mood. Henry Holt and Company,
LLC, pp. 200-205.
9. Sethi, P.D. (1996). Water soluble and fat soluble vitamins, Quantitaive Analysis of
Pharmaceutical Formulations, CBS Publisher & Distributors, New Delhi. pp. 1-200.
10. Fried, B., J. Sherma (1999). Analysis of hydrophilic vitamins, 4th ed,
chromatographic science series, Volume 81, Marcel Dekker, New York. pp. 215255.
11. D.E. Metzler, E.E. Snell, J. Am. Chem. Soc. 77 (1955) 2431.
12. R. L. Gustafson and A. E. Martell, Arch. Biochern. Biophys. 68, 485 (1957).
13. Y. Matushima and A. E. Martell, J. Amer. Chem. Soc., 89, 1322 (1967).
14. W. Korytnyk and R. P. Singh, J. Amer. Chem. Soc., 85, 2813 (1963).
15. O. A. Gansow and R. H. Holm, Tetrahedron, 24, 4477 (1968).
16. R. D. Lapper, H. H. Manisch and I. C. P. Smith, Can. J. Chem., 53, 2406(1975).
17. F. Hanic, Acta Crysta11ogr, 21, 332 (1966).
18. N.G. Furmanova, Zh.I. Berdalieva, T.S. Chernaya, V.F. Resnyanskii, N.K. Shiitieva,
K.S. Sulaimankulov, Crystallography Reports, 54(2) (2009) 228.
19. F. Binkley, C.K. Olsen, J. Biol. Chem., 185 (1950) 881.
20. J.B. Longenecker, E.E. Snell, J. Amer. Chem. Soc., 79 (1957) 142.
21. M.S. El-Ezaby, F.R. El-Eziri, J. Inorg. Nulc. Chem., 38 (1976) 1901.
22. J.S. Hartman, E.C. Kelusky, Can. J. Chem., 57 (1979) 2118.
23. A. Mosset, F. Nepveu-Juras, R. Haran, J.J. Bonnet, J. Inorg. Nucl. Chem., 40 (1978)
1259.
24. Eliot, A. C.; Kirsch, J. F. Annu. Rev. Biochem., 73, 383–415 (2004).
25. Makhyoun, M. A.; Al-Salem, N. A.; El-Ezaby, M. S. Inorg. Chim. Acta (1986), 123,
117–125.
26. Back, D. F.; de Oliveira, G. M.; Lang, E. S. J. Inorg. Biochem. (2006), 100, 1698–
1704.
27. Bonfada, E.; Oliveira, G. M.; Back, D. F.; Lang, E. S. Anorg. Allg. Chem.(2005),
631, 878–881.
28. Rao, S. P. S.; Varughese, K. I.; Manohar, H. Inorg. Chem. (1986), 25, 734–740.
29. Neelakantan, M. A.; Sundaram, M.; Thalamuthu, S.; Nair, M. S.J. Coord. Chem.
(2010), 63, 1969–1985.
30. Casas, J. S.; Castineiras, A.; Condori, F.; Couce, M. D.; Russo, U.; Sanchez, A.;
Sordo, J.; Varela, J. M. Polyhedron (2000)19, 813–819.
31. Mathews, I. I.; Manohar, H. J. Chem. Soc., Dalton Trans. (1991), 2139–2143.
32. Chamayou, A. C.; Neelakantan, M. A.; Thalamuthu, S.; Janiak, C. Inorg. Chim.
Acta (2011), 365, 447–450.
33. Dey, S.; Banerjee, P.; Gangopadhyay, S.; Vojtí_sek, P. Transition Met. Chem.
(2003), 28, 765–771.
34. Acquaye, J. H. K. A.; Richardson, M. F. Inorg. Chim. Acta 1992, 201, 101–107.
35. Neelakantan, M. A.; Nair, M. S. Iran. J. Chem. Chem. Eng. 2004, 23, 97–102.
115
36. Lakshmi, G. C.; Ananda, S.; Netkal, M.; Gowda, M. Synth. React. Inorg. Met-Org.
Nano-Met. Chem. 2009, 39, 434–440.
37. Back, D. F.; Ballin, M. A.; Oliveira, G. M. J. Mol. Struct. 2009, 935, 151–155.
38. M. A. Neelakantan, M. Sundaram, and M. Sivasankaran Nair, J. Chem. Eng. Data
(2011), 56, 2527–2535.
39. J.M. Sánchez-Ruiz, J. Llor, M. Cortijo, J. Chem. Soc., Perkin Trans. II (1984) 2047.
40. V.Kh. Sabirov, A.S. Batsanov, Yu.T. Struchkov, M.A. Azizov, A.A. Shabilalov,
A.S. Pulatov, A.A. Shabilalov, A.S. Pulatov, Koord. Khim. 10 (1984) 275.
41. V.Kh. Sabirov, Yu.T. Struchkov, Kh.Kh. Khakimov, Sh.A. Nurmukhamedov, Uzb.
Khim. Zh. (1997) 3.
42. J.S. Casas, E.E. Castellano, F. Condori, M.D. Couce, A. Sánchez, J. Sordo, J.M.
Varela, J. Zuckerman-Schpector, J. Chem. Soc., Dalton Trans. (1997) 4421.
43. S.P. Sudhakara Rao, K.I. Varughese, H. Manohar, Inorg. Chem. 25 (1986) 734.
44. V.Kh. Sabirov, I.A. Litvinov, A.N. Yunuskhodzhaev, Koord. Khim. 17 (1991) 44.
116
CHAPTER 12
12-1- Enalapril Maleate
Enalapril (marketed
marketed as Vasotec in the USA and Enaladex in some other countries) is
chemically described as [(2S)-1-[(2S)-2-[[(1S)-1-(ethoxycarbonyl)-3-phenylpropy]
[(2S)
phenylpropy] amino]
propanoyl] pyrrolidin-2- carboxylic acid (Z)-butenedioate]
(Z) butenedioate] maleate, which is a derivative of two
amino-acids, i.e., L-alanine
alanine and L-proline
L
(Fig. 12-1).
). Its molecular weight is 492.53 g/mol. It is
◦
a white to off-white
white crystalline, odorless powder which melts in the range of 143-144
143
C [1]. The
rotation around the proline amide bond in enalapril is hindered at room temperature. In the solid
state, enalapril
pril was found to be exclusively in the trans form around the amide bond [2,
[ 3]. In
solution [4],
], enalapril can exist as cis and trans rotamers. The cis-trans
trans interconversion of
enalapril in solution, like that of other proline dipeptides, has a relaxation time of the order of
minutes [5, 6].
]. The solubility of enalapril maleate in water is poor but it is highly soluble in
methanol. Enalapril maleate is a prodrug; following oral administration, it is bioactivated by
hydrolysis of ethyl ester to enalaprilat, which is the active angiotensin converting enzyme
inhibitor. It lowers peripheral vascular resistance without causing an increase in the heart rate. It
is an ideal drug for hypersensitive patients who are intolerant to beta-blockers.
beta blockers. The drug is used
for treating
reating high blood pressure or hypertension in adults, children and congestive heart failure
[7, 8].
Fig. 12-1:: Structure of Enalapril Maleat (Enal) ligand.
ligand
The therapeutic importance of enalapril maleate was behind the development of
numerous methods for its determination. The methods adopted to the analysis of enalapril
maleate include high-performance
performance liquid chromatography [9-11],
[
], capillary electrophoresis [12],
[
liquid chromatography- tandem mass spectrometry [13],
[
polarography [14
14], atomic absorption
spectrometry [15]] and membrane selective electrodes [16].
]. Few spectrophotometric methods
have also been reported for the determination of enalapril maleate in commercial dosage forms.
The cited drug after dissolving in distilled water exhibits a maximum absorbance at 207 nm and
117
this property has been exploited to develop a UV method for its quantitation [192]. Enalapril
maleate reacts with 2, 4-dinitroflurobenzene at pH 9 yielding a colored product which absorbs
maximally at 356 nm forming a basis for its determination. Spectrophotometric methods based
on the ternary complex formation between copper (II), eosin; palladium (II), eosin [193] and
enalapril maleate have been reported. Three simple, rapid, novel and sensitive
spectrophotometric methods were developed for the determination of Enalapril maleate in
pharmaceutical formulations. The first method is based on the formation of pale yellow colored
ion pair complex between Enalapril and Bromothymol blue reagent [194], which is readily
extracted into Dichlolomethane solvent and determined spectro photometrically at 410 nm
(λmax). The second and third methods are based on the oxidation followed by complex formation
[195]. This involves oxidation of Enalapril maleate by Iron (III) FeCl3 and the produced iron (II)
reacts with Potassium Ferricyanide and 2, 2’-Bipyridyl reagents forming bluish green colored
chromogen at 778 nm and orange red colored chromogen at 520 nm, respectively [196]. These
are simple sensitive, rapid since it is a single step procedure and low costing without loss of
accuracy.
The spectrophotometric determination of enalapril procedures by measuring maximum
absorbance are based on ternary complex formation. The first ternary complex (copper (II),
eosin, and enalapril) was estimated by two methods. The first depends on its extraction with
chloroform measured at 533.4 nm and Beer's law was obeyed in concentration range from 56 to
112 μg ml−1. The second method for the same complex depends on its direct measurement at
pH 5 and after addition of methylcellulose as surfactant the value obtained was at 558.8 nm
[197]. The sodium enalapril complex can be made by reacting I with 1,1'-carbonyldiimidazole
(CDI) to form anhydride (II), which reacts with the sodium salt of L-Proline to produce crude
sodium enalapril III. Crude enalapril III may react with sodium iodide to produce essentially
pure sodium enalapril iodide complex (IV) [198]. Formation constants for the zinc (II) and
copper (II) complexes of maleate, enalapril maleate and lisinopril have been measured
potentiometrically at 37 °C [199].
Scheme 12-2: sodium enalapril complex formation.
118
REFERENCES
1. Ip DP, Brenner GS, in: K. Florey (Ed.), Analytical Profiles of Drug Substances,
Academic Press Orlando FL. ;207–243(1987).
2. Y. In, M. Shibata, M. Doi, T. Ishida, M. Inoue, Y. Sasaki and S. Morimoto, J.
Chem. Sot., Chem. Commun., (1986)437.
3. G. Precigoux, S. Geoffre and F. Leroy, Acta Crystallogr., Sect. C, 42 (1986) 1022.
4. Y. Sakamoto, Y. Sakamoto, I. Oonishi and T. Ohmoto, J. Mol. Struct., 238 (1990)
325.
5. J. F. Brandts, H. R. Halvorson and M. Brennan, Biochemistry, 14 (1975) 4953.
6. J. Jacobson. W. Melander. G. Vaisnvs and Cs. Horvath. J. Phys. Chem, 88 (1984)
4536.
7. Cleary, J. D.; Taylor, J. W.; Drug Intell. Clin. Pharm. , 20, 177(1986).
8. Todd, P. A.; Heel, R. C.; Drugs , 31, 198 (1986).
9. Thongnopnua, P. and Poeaknapo, C. J. Pharm. Biomed. Anal., 37:763–69 (2005).
10. Tajerzadeh, H. and Hamidi, M.J. Pharma. Biomed. Anal., 24:675–80 (2001).
11. Anzenbacherova, E., Anzenbacher, P., Macek, K. and Kvetina, J. J. Pharm.
Biomed. Anal., 24:1151–6(2001).
12. Qin, X-Z., Dominic, P.I. and Tsai, E.W. J. Chromatogr. A., 626:251–8 (1992).
13. Gu, Q., Chen, X., Zhong, D. and Wang, Y. J. Chromatogr. B., 813:337–42 (2004).
14. Razak, O.A., Belal, S.F., Bedair, M.M., Barakat, N.S. and Haggag, R.S. J. Pharm.
Biomed. Anal., 31:701–11(2003).
15. Ayad, M.M., Shalaby, A.A., Abdellatef, H.E. and Hosny, M.M. J. Pharm. Biomed.
Anal., 28:311–21(2002).
16. Aboul-Enein, H.Y., Bunaciu, A.A., Bala, C. and Fleschin, S. Anal. Lett., 30:1999–
2008 (1997).
17. Chandwani, O.D., Dahibhati, P.P., Kadam, S.S. and Dhaneshwar, S.R. Indian
Drugs, 33:401–2 (1996).
18. Ayad, M.M., Shalaby, A.A., Abdellatef, H.E. and Hosny, M.M. 2003. Anal.
Bioanal. Chem., 375:556–60.
19. R.C Mackenzie, Pure Appl. Chem, 57, 1737 (1985).
20. Vogels Qualtitative Inorganic Analysis, 7thedition; pg.111-112.
21. M. Manoranjani, K. Kamala Karuna, International Journal of Research in
Pharmaceutical and Biomedical Sciences, Vol. 2(4) Oct - Dec 2011.
22. Magda M. Ayad, Abdalla A. Shalaby, Hisham E. Abdellatef, Mervat M. Hosny,
Journal of Pharmaceutical and Biomedical Analysis, Volume 28, Issue 2, 15 April
2002, Pages 311-321.
23. K. S. Keshava Murthy, Andrew Burchat, Gamini Weeratunga, Brantford Chemicals
Inc., Patent No: 5637730, Jun.10, (1997).
24. J.A. Balman, G.L. Christie, J.R. Duffield, D.R. Williams, Inorganica Chimica Acta,
Volume 152, Issue 2 ,81-90 (June 1988) .
119
About the Authors
Moamen
Refat born in Egypt. He received his B.S.
(1992), M.Sc. (1998)) and Ph.D (2002) degrees from
Zagazig University (Egypt
Egypt). He joined Taif University
(Saudi Arabia) in 2008.
2008 He is the author of over 100
research papers published in highly impacted journals in
the field of Inorganic chemistry. He awarded many
international scientific prizes include young Arab
researchers prize
rize (Abdul hameed shoman foundation), the
Arabian prize in chemistry for young researchers,
researchers the Taif
University prize for distinguished researcher (2009-2011)
and the Taif University prize for scientific publication
(2009-2011).. His research interests include charge-transfer,
metal-drug, metal-acid,
acid, metal-dye
meta
and shiff base
complexes.
Samy El-Megharbel born in Egypt. He received his B.S.
(2000), M.Sc. (2005) and Ph.D (2009) degrees from
Zagazig University (Egypt
Egypt). He joined Taif University
(Saudi Arabia) in 2013.. He is the author of over 15 research
papers published in highly impacted journals in the field of
Inorganic chemistry. He awarded the Zagazig University
prize for the best Ph.D
D thesis.
thesis His research interests include
metal and metal-drug
drug complexation.
complexa
Abdel Majid Adam born in Sudan. He received his B.S.
(1996), M.Sc. (1999) and Ph.D (2002) degrees from the
University of Khartoum (Sudan). He joined the Teachers
College in Taif in 2003 and in 2008 moved to the Taif
University (Saudi Arabia).
Arabia) His teaching experience of more
than 15 years. He is the author of over 30 research papers
published in highly impacted journals in the field of
Inorganic chemistry. He awarded the Taif University prize
for scientific publication in 2011 and 2012.
2012 His research
interests include
de charge-transfer
charge
complexation, metal-drug
complexation and uranium extraction.
extraction
120

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