Fluoroquinolones : An Overview

Mr.Sandesh R Lodha

A vast array of fluoroquinolones having excellent broad-spectrum activity forms an invaluable part of the present anti-infective armoury of the clinicians.

A number of these compounds are today's blockbusters of the antibacterial market due to their therapeutic efficacy having tolerable side-effects and thus, challenging the predominance of well- established β-lactam antibiotics which are becoming more prone to the resistant pathogenic bacteria.

The fluoroquinolones are the fastest growing antibacterial class in terms of global revenue, increasingly being used in both the hospital and community sectors to treat a broad range of infections¹.

Report Highlights: Of the 20 antibacterials lately introduced into the clinic seven are   fluoroquinolones and of which four are expected to dominate the market by 2010.However, the US patent expiry of Bayer's blockbuster Cipro, is set to change the dynamics of this sector while novel compounds are increasingly favoured in the light of drug resistance.

The fluoroquinolone market is heavily dominated by ciprofloxacin and levofloxacin, which together command 65% ($3.3 billion) of global sales². The broad spectrum of pathogen activity exhibited by these compounds, alongside their wide range of available formulations, creates significant challenges for companies looking to introduce novel products.

Since the discovery of nalidixic acid (1962) ^(3.4), the development of fluoroquinolones has experienced an exponential growth and is being continued with more vigour to obtain better drugs having multifunctional action.

The current developments of the chemical and biological aspects of fluoroquinolones in a chronological manner touching upon their antibacterial properties based on the structure- activity relationship while pointing out to their mode of action.

This provides an insight into a variety of approaches resulting in elegant manipulations of their basic skeleton and some breakthroughs in the synthetic strategies of a few widely- used drugs and these have immensely  helped in accelerating their market growth as well as continuing research for newer fluoroquinolones.

Since the mode of action of fluoroquinolones is different from β-lactams and their transportation to the target site is slow, several dual action quinolonyl-β-lactams (Penicillins, Cephalosporins, Penems, Cephems, and Carbapenams etc.) have come as a major breakthrough among the "hybrid antibiotics". While focusing on the multifunctional activities of such compounds, this review briefly points out to the current trends in drug design and development of newer therapeutic molecules, which hold future promises in combating the fight against drug-resistant bacteria as it still remains to be won.

History⁵

The evolution of quinolones actually emanated from the discovery of nalidixic acid in 1962 ⁶ as a by-product of antimalarial research, the first representative of the quinolones which was found effective against some Gram-negative Gr (-ve).

Nalidixic acid became the lead compound ³ for medicinal chemists for structural modifications to get many newer fluoroquinolones in order to get rid of its three major shortcomings¹-

 i) narrow spectrum covering Gr (-ve) organisms only

(ii) Achieves inadequate tissue levels for systematic infections and

(iii) Bacterial resistance development.

This opened the flood gate for synthesizing newer and more interesting fluoroquinolones. Out of more than 8000 analogues of fluoroquinolones synthesized ^7,8,9,10 bearing variety of rjng systems, a few dozens have been established in the market, and more are in the horizon to be introduced. Such an explosive growth of this group of compounds occurred mainly due to three factors; firstly, an unprecedented mode of action depending on inhibition ability of susceptible micro-organisms to shape their DNA for storage or replication; secondly, their potency and antimicrobial spectrum being equally comparative to the desired fermentation-based semi-synthetic antibiotics; and finally, their chemical structure being simple, a large number of analogues could be prepared following simple synthetic sequences in a cheaper way from readily available intermediates or chemicals.

Further, rapid progress has been made towards broadening their spectrum of activity based on structure-activity relationship (SAR) to treat various systemic infections other than urinary tract infections (UTI) ¹¹, improving their pharmacokinetic properties ⁴ and to reduce adverse reactions, especially central nervous system (CNS) side-effect; which is common among these group of compounds.

Chronological Development Of Fluoroquonilones

An alkaloid having quinolone structure was first prepared by Price et al.(1949) but it possessed no biological activity. In 1960 , Barton et al ¹² . isolated 6-chloro-1H-ethyl-4-oxo-quinoline-3- carboxylic acid during antimalarial research, which showed antibacterial activity. Thereafter, the era of quinolone began with the discovery of nalidixic acid in 1962 having naphthyridine nucleus⁽¹³⁾ in it and continued to flourish by analog developments with introduction of oxolinic acid, cinoxacin ,pipedimic acid etc, but none of these were acceptable to the medical profession. The benzopyridone nucleus (quinolone) proved to be more responsive to chemical manipulation in order to enhance antibacterial potency and subsequent discovery of fluorine atom and piperazinyl ring on the quinolone ring viz norfloxacin,pefloxacin, ciprofloxacin , ofloxacin, flumequine, revolutionized the chemistry and clinical importance of fluoroquinolones. There are some quinolones which are in different stages of development such as prulifloxacin, nadifloxacin, balofloxacin, PD 140288, CEC-222, CS-940, HSR-903, DW-116 [22-25] This gave further impetus growth of fluoroquinolones ,and thousands of derivatives or analogs are being synthesized based on the structure-activity relationship (SAR) by chemical modifications and among them some are recognized as the drug of choice because of their enhanced antibacterial spectrum as well as activity against anaerobic bacteria. Some prominent members of this group are arranged chronologically in Fig.

Newer subclasses of fluoroquinolones are also under investigations ¹⁴, important among them are desfluorinated [C-6 fluorine replaced by amino] quinolones and nitroquinolones Also, in mid 1980's to mid 1990's, a lot of dual action hybrids formed by joining fluoroquinolones with β-lactam antibiotics through various linkages viz. esters, carbamate, quaternary ammonium salts, amides, ether, thioether etc. were synthesized which were having excellent antibacterial spectrum, and some of these are under final stage of clinical trials.

Moreover, their pharmacokinetic properties were also improved leading to less adverse reactions. Thus, continuous efforts were directed to further modify the quinolone pharmacophore with more complex newer fluoroquinolones viz. danofloxacin, trovafloxacin , pazufloxacin , moxifloxacin , clinafloxacin  etc. Some of

these currently used drugs are shown in Fig.

Classification:

Two main classifications for fluoroquinolones based on chemical structure  and biological properties  respectively has been described by Bryskier & Chantot ¹⁵ , which logically embraces the majority of active compounds known till date.

Chemical classification of Fluoroquinolones ¹⁶

Biological classification of fluoroquinolones ¹⁵

Classification On The Basis Of Spectrum Of Activity ^{( 17,18)}

Table No. 1

Chemical structures of some commonly used fluoroquinolones

Structure-Activity Relationship (^{1, 19,21)}:

Position 1^(19,20):

Ø Earlier study indicated that substitution at N-1 position is important for Anti-bacterial activity .

Ø QSAR analysis of a set of N-1 allyl and alkyl derivatives suggested and optimum STERIMOL length of 0.42 nm , corresponding approximately to an ethyl group.

Ø STERIMOL is a program that calculates a set of five parameters characterizing size and shape of a substituent .

Ø STERIMOL length is defined as length of substituent along the axis of bond between the substituent and the parent molecule.

Ø Subsequently, the discovery of potent quinolones with N-1 phenyl and N-1 cyclopropyl substitutions indicated that with respect to an N-1 substituent, in addition to steric bulk , there are other factors such as electronic- π donation and ideal spatial effects that also have a great influence on their biological activities .

Ø Introduction of a t-butyl group at N-1 produced quinolones with enhanced activity against gram positive bacteria with minor reduction of activity against gram negative bacteria .

Ø In general , cyclopropyl group appears to be optimum for activity. e.g Ciprofloxacin.

Position - 3 :

Ø Position 3 and 4 , having a link between the carboxylic acid group and the keto group are generally considered necessary for binding of quinolones to DNA gyrase .

Ø Classical studies have produced no active quinolone with a significant modification of C-3 carboxylic acid group , with exception of groups which are converted in vivo to carboxylic acid group .

Position - 4 :

Ø Position - 4 has not been extensively explored and replacement of 4- keto group with other groups has generally produced inactive or weakly active compounds.

Position - 5 :

Ø Compounds with small substituents such as  nitro, amino , halo,     alkyl groups have been synthesized . Among them , C-5 amino group enhances absorption  and / or tissue distribution . e.g Sparfloxacin .

Ø The incidence of photo toxicity of Sparfloxacin is the lowest of the fluoroquinolones , because of the presence of the 5- amino group , which counteracts the effect of the 8- fluoro substituent .

Position - 6 :

Ø Of various C-6 substituents,  H, Cl  , Br , F , CH₃ , S- CH_3, CO CH₃  , CN , NO₂  etc the addition of a fluorine atom resulted in a dramatic increase in anti-bacterial potency .

Ø Fluoro group at C-6 seems to improve both the DNA gyrase complex binding ( 2 to 17 folds ) and cell penetration ( 1 to 70 folds ) of the corresponding derivatives with no substitution at C-6.

Position - 7 :

Ø C-7 piperazinyl group in addition to C-6 fluorine substituent has anti-bacterial  potency for superior to that of earlier classical quinolones against both gram-positive and gram-negative bacteria .

Ø In general, quinolones  with small or linear C-7 substituents ( H ,Cl , CH_{3 ,} NH₂ -CH₂-CH₂- NH₂ , NH- CH_{3 ,} NH-NH₂  ) possess moderate to weak anti-bacterial activities .

Ø Various substitutions tried at C-7 position are -                          

•  substituted piperazinyl
•  substituted pyrrolidinyl
•   substituted morpholinyl

Ø In general, the substitution of methyl at C-4 position of the piperazinyl group enhances gram-positive anti-bacterial activity with slight decrease in gram-negative activity .

Position - 8 :

Ø C-8 fluoro or chloro derivatives are more active in-vivo , owing  to better oral absorption .

Ø Oxygen substituent at C-8 position , where substituent is part of ring system has been shown to have better in vivo efficacy .

Ø C-8 methoxy or ethoxy group appears to increase the spectrum of activity .

Ø C-8 methoxy ( e.g Gatifloxacin ) has been shown to contribute significant activity against anaerobes .

Influence of substituent group on adverse effects and drug interaction of quinolones:

Table No. 2

Isomers Of Fluoroquinolones ¹

Most recent fluoroquinolones available for clinical use are either chiral or racemic mixtures. However, the S(-) enantiomer of ofloxacin is currently under introduction in market. Chiral recognition is important when the chiral group is in close proximity to the quinolone core such as, N-1 or C-7. When the chiral groups are further away, only a minor improvement in antibacterial activity over their antipodes have been observed. Ofloxacin is a tricyclic compound with a methyl group at the asymmetric C-3 position in the oxazine ring. The S(-) ofloxacin (levofloxacin) isomer is approximately 8 to 28 times more potent than the R(+) ofloxacin and twice as active as ofloxacin . The stereochemistry affects enzymatic activity rather than other factors such as drug penetrations, since inhibitory activity against purified DNA gyrase also differs in the same proportion between these two orientations of ofloxacin. The two enantiomers demonstrated a similar pattern of specific binding. Four S-isomers and only 2Risomers bind to DNA receptors.

Temafloxacin is a racemate with a chiral centre at C-3' of the 7-piperazinyl ring. Temafloxacin and its R and S enantiomers possess identical antibacterial inhibitory effects on the supercoiling activity of E coli H 560 DNA gyrase and comparable potency in vivo against S. aureus, P. aeruginosa and E. coli infection in mice .

 Table No. 3   Pharmacokinetics Of Fluoroquinolones ^{(23, 24, 25, 28, 31)}

Ø The maximum concentration ( C max ) is important because the Fluoroquinolones effectiveness is concentration-dependant²⁶ . It has been shown that in order for bacteria to be highly susceptible to Fluoroquinolones and prevent resistant mutants , the maximum concentration must be 10 times that of the minimum inhibitory ( MIC)  concentration when treating against gram-positive bacteria.

Ø For gram-negative bacteria, desired ratio of area under curve (AUC) to minimum inhibitory concentration (MIC) is greater than 125 and for gram-positive bacteria, AUC to MIC ratio should be atleast 30.

Drug , Indication , Dose , Duration of therapy chart for some Fluoroquinolones ^(24,26) : Table No. 4

CAP = community acquired pneumonia ²⁹, AECB = acute exacerbations of chronic bronchitis ³⁰, UTI = urinary tract infections

Side-Effects³² :

Ø Achilles Tendonitis :- Both older and newer fluoroquinolones have been shown to be associated with arthropathy in weight bearing joints . Studies have shown erosion and permanent lesions of cartilage due to quinolone use in animals .

Ø Cardiac :- QT prolongation is thought to be due to halogen substitution at the number 8 position ( e.g Moxifloxacin )

Ø Gastrointestinal :- Most common side-effects are nausea , vomitting and diarrhoea , with an occurrence rate ranging from 3 to 17 percent .

Ø CNS :- Effects such as insomnia , dizziness and anxiety have been reported in 0.9 to 11 percent patients .Seizures are a rare occurrence but have been increasingly reported when used with Theophylline or with NSAID's .

Ø Crystaluria :- Associated with fluoroquinolones except Levofloxacin , Gatifloxacin³⁴,Moxifloxacin , and Trovafloxacin . Patients are instructed to drink plenty of water.

Ø Liver Toxicity :-  In 18 months post-approval follow up by US Food and Drug Administration  (FDA)  for Trovafloxacin 140 cases of liver toxicity were found .

Ø Phototoxicity :- Most likely to occur with the use of Ciprofloxacin , Lomefloxacin and Norfloxacin .

Contraindications^{( 24,33)} :

Ø   Due to effect on cartilage , fluoroquinolones are contraindicated in pregnant or nursing mothers and children under the age of 18.

Ø  Reports of occasional hypersensitivity to quinolone have restricted their clinical use in hypersensitive patients .

Ø Patients with severe renal dysfunction and epilepsy .

Drug Interactions ^{( 24,33)} :-

 Potential interactions between quinolones and other drugs are shown in the following table .

Table No. 5

Mode Of Action

The bactericidal effect of fluoroquinolones like earlier quinolones are mediated through their ability to block activity of bacterial DNA gyrase enzyme system. The function of this enzyme is to enable the long bacterial DNA to fit into the cell through supercoiling. In linear as well as circular DNA, the two strands of polynucleotides are coiled around each other so as to form a double helix. There are approximately 10 base pairs per turn of helix. Each time one of the strands of DNA winds with each other and make a link. Thus a circular DNA containing several base pairs is expected to contain about 500 links i.e. its linking number L is 500. When L in such a molecule is less than 500, the molecule becomes strained. To relieve the strain, it supercoils just as twisting a thread will result in further coiling making a supercoiled structure. The supercoiled DNA occupies less space than the relaxed DNA. In cells and in microorganisms, enzymes called topoisomerases control super coiling e.g. Gyrase. The inactivation of gyrase kills the bacterial cell by distrupting the DNA supercoiling so that DNA can no longer be contained within the cell and it bursts.

The DNA gyrase is made up of two A and B sub units. Sub unit A is coded by the gyr   A gene and the single sub unit is 9700 daltons.

The sub unit B has a molecular size of 89,835 daltons and is coded by the gyr B gene. The effect of quinolones on DNA replicative enzymes in mammalian cells has been extensively investigated. The molecular mechanism of inhibition of DNA gyrase by quinolones has been studied extensively ³⁵. Quinolones bind co-operatively to DNA gyrase-induced specific sites on relaxed DNA. These investigations have shown that quinolones do not bind to DNA gyrase at its inhibitory concentration but bind preferentially to single-stranded DNA. This showed that quinolones bind poorly to relaxed, double stranded DNA but bind specifically to a saturable site on supercoiled DNA in a highly co-operative manner and that quinolone binding to relaxed double stranded DNA is enhanced by DNA gyrase. Quinolones are bactericidal at concentrations above MIC. The bactericidal action of older quinolones such as nalidixic acid was inhibited by the simultaneous addition of rifampin, suggesting that protein synthesis was a requirement for bactericidal action for E. coli even in presence of rifampin or chloramphenicol. It was also shown that these compounds were bactericidal for non-dividing cells also.

New quinolones such as ciprofloxacin is less active against Gr (+ve) bacteria than against Gr (– ve) suggesting the bactericidal mechanism of ciprofloxacin against Gram (+ve) and Gr (-ve) bacterial cell is different. This difference of mechanism of killing Gr (-ve) and Gr (+ve) bacteria may be the reason of inability of ciprofloxacin to achieve bactericidal cure in Staphylococcal infections.

Therefore, it appears that some of the newer fluoroquinolones like sparfloxacin, tosufloxacin and lomefloxacin etc. also damage the bacterial cell memberane which leads to loss of cell contents. This unique mode of action of newer fluoroquinolones is mainly responsible for infrequent occurrence of bacterial resistance to these drugs.

Very recently, it is investigated that the mode of action of quinolones involves interaction with both DNA gyrase, the originally recognised drug target and topoisomerase IV ³⁵, a related type II topoisomerase . In a bacterial cell, these 2 enzymes often differ in their relative sensitivities to many quinolones and commonly DNA gyrase is more sensitive in Gram (-ve) bacteria and topoisomerase IV more sensitive in Gram (+ve) bacteria. Usually the more sensitive enzyme represents the primary drug target determined by genetic tests, but poorly understood exceptions are  here.

X-ray crystallographic studies of a fragment of the gyrase A subunit as well as of yeast topoisomerase IV ³⁵, have revealed domains that are likely to include DNA and quinolone have been reported.

The inhibition of DNA synthesis by quinolones requires the targeted topoisomerase to have DNA cleavage capability and collisions of the replications fork with reversible quinolone –DNA topoisomerase complexes³⁶ convert them to an irreversible form. However the molecular factors that subsequently generate DNA doublestrand breaks from irreversible complexes and that probably initiate cell death have yet to be defined.

Cases Of Resistance :-

Ø In the recent,  past there have been increasing number of cases of resistance against fluoroquinolones due to many reasons such as

•   Incomplete treatment with required doses and duration
•   Overdosage
•   Excessive and improper use of fluoroquinolones when not  required
•   Development of mutant strains of causative bacteria

Resistance Mechanism :-

According to the present state of knowledge the ---

Ø Important mechanism -- Alteration in DNA gyrase and topoisomerase IV and decreased intracellular accumulation of the drug due to modifications of membrane proteins .

Ø Single point mutation in gyr A that codes for a type II topoisomerase subunit A is most common³⁷.

Ø Reduction of gyrase affinity for drug

Ø Decreased penetration due to loss of key membrane proteins

Ø Cross resistance among fluoroquinolones -- resistance to one quinolone usually confers resistance to entire class.

Some Recent Trends In Chemical Modifcations ⁽¹³⁾:

Table No. 6

Summary

Fluoroquinolones are the fastest growing antibacterial class in terms of global revenue. Current development of fluoroquinolones is based on structure activity relationship while pointing out to their mode of action. However, increased indiscriminate prescribing has led to recent occasional emergence of fluoroquinolone resistant bacteria, which necessitates the search for newer drugs with efficacy against resistant strains.

References

1.  S.K Bhanot,M. Singh ,and N R Chatterjee : The Chemical and Biological Aspects of Fluoroquinolones : Reality and Dreams , Current Pharmaceutical design, vol. 7 , pp. 313-337, 2001
2. Commercial prospective: Fluoroquinolones – Established products drive the market growth, Jan – 2004, ( www.marketresearch. Com )
3. John M. Beale , Jr. , "Anti-infective agents",chap-8, In Wilson and Gisvold's Textbook of Organic, Medicinal and Pharmaceutical Chemistry , J.H and Beale J.M (Eds.) ,11thEd.,  Lippincott William Publisher , Baltimore (USA),pp. 247 -252,2004
4. Eric M Scholar ; Fluoroquinolones : Past , Present and Future of a Novel Group of Antibacterial Agents, American Journal of Pharmaceutical Education , vol. 66 , pp. 165-172 , 2003
5. Peter Ball ; Quinolones – Natural history or natural selection , J. Antimicrobial Chemotherapy , vol. 46 , pp. 17-24 , 2000
6. Lesher, G. Y.; Foelich, E. J.; Garnett, M. D.; Baily,J. H.; Brundage, P. R. J. Med. Chem., vol. 5, pp. 259. 1962.
7. Chaitanya G. Dave and Hardik M. Joshipura ; Microwave assisted Gould - Jacob reaction: Synthesis of 4- quinolones under solvent free conditions, Indian.J.Chem. , vol. 41B , pp. 650 - 652 , 2002
8. Yeh-Long Chen , Kuo-Chang Fang , Jia-Yuh Sheu ,  Shu-Lin Hsu , and Cherng-Chyi Tzeng ; Synthesis and Antibacterial Evaluation of Certain Quinolone Derivatives , J.Med.Chem ,  vol . 44 , 2374 - 2377 , 2001
9. Jian-hui Liu and Hui- yuan Guo ; Synthesis and Antibacterial Activity of 7- ( substituted pyrrolyl -) -1-(substituted amino -6- fluoro-1,4 dihydro- 4-oxo- 3- quinolinecarboxylic acids ,  J.Med.Chem , vol.  35 , pp. 3469 - 3473 , 1992
10. Hirosato Kondo , Masahiro Taguchi , Yoshimasa Inoue, Fumio Sakamato , and Goro Tsukamoto , Synthesis and  Antibacterial Activity of Thiazolo - , Oxazolo- ,and Imidazolo [3,2-a][1,8] naphthyridinecarboxylic Acids ; J.Med.Chem. , vol.   33 , pp. 2012 - 2015 , 1990
11. Nicolle, L.E., "Use of quinolones in urinary tract infection and prostatitis," in The Quinolones, Academic Press, New York NY , pp. 183-202 , 1998
12. Giguere, R. J., Bray, T.L. and Duncan, S.M., Tetrahedron Lett., vol. 27, pp. 4945, 1986
13. K. Mogilaiah , K Srinivas and G Rama Sudhakar ; Chloramine T mediated synthesis of 1,8-naphthyridinyl-1,3,4-Oxadiazoles ; Ind. J. Chem. , vol. 43B , pp. 2014 - 2017 , 2004.
14. hu, D. T. W.  & Fernandes, P. B. In Advances in Drug Research,  B. Testa. Ed., Academic Press, London ,  Vol. 21, pp. 39-144. 1991
15. Bryskier, A.; Chantot, J. F. Drugs, vol. 49, pp. 16, 1995
16. Naber, K. G.; Adam, D. Int. J. Antimicrob. Agents, vol. 10,  pp. 255 , 1998 .
17. Andriole, V. T. Drugs, vol. 58, pp.1 , 1999
18. E.M. and Reeves, D.S., "Quinolones," in Antibiotic and Chemotherapy, Churchill Livingstone, New York NY , pp. 419-452 , 1997
19. Daniel T. W Chu and Prabhavathi B. Fernandes ; Structure- Activity Relationships of the Fluoroquinolones,  Antimicrobial Agents and Chemotherapy , vol. 33 , pp. 131- 135 ,  1989
20. Masateru Ohta and Hiroshi Koga ; Three dimensional Structure Activity Relationship and Receptor Mapping of  N1 - substituents of Quinolone Antibacterial , J. Med. Chem. , vol. 34 ,pp. 131 -139 , 1991
21. Yasu1ori Tsuzuki , Kyoji Tomita , Koh-ichiro Shibamori , Yuji Sato , Shigeki Kashimoto and Katsumi Chiba ; Synthesis and Structure-Activity Relationships of Novel  7- substituted 1,4 dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acids as Anti-tumor agents , part-2 , J.Med.Chem. , vol.47, pp. 2097 - 2109  , 2004
22. A.Prakash , V. Kacker and Shyam S. Sharma ; How and Why Fluoroquinolones , Drugs: News and Views , vol. 3 , pp. 133 -139 , 1995 
23. Fluoroquinolones - Drug Class Review , Oregon State University ,  pp. 1 - 9 , 2002  ( through internet - www.google.com)  
24. Joseph Bertino and Douglas Fish ; The Safety Profile Of The Fluoroquinolones , Clinical Therapeutics, vol. 22 , pp. 798 - 815 , 2000
25. Caroline M.Perry , Douglas Ormrod , Miriam Hurst and  Susan V. Onrust , Gatifloxacin A review of its use in  the management of bacterial infections ; Drugs  , vol. 62 , pp. 169 - 207 , 2002
26. Eliopoulos, G.M., "In vitro activity of new quinolone antimicrobialagents," in Microbiology, Amer. Soc. Microbiol., pp. 219-221 , Washington DC , 1986
27. Catherine M. Oliphant , Gray M. Green ; Quinolone : A Comprehensive Review , American Family Physician , pp. 1 - 11 , 2002 
28. Schentag, J.J., Nix, D.E. and Wise, R., "Pharmacokinetics and tissuepenetration of quinolones," in The New Generation of Quinolones,Marcel Dekker, NewYork NY, pp.189-222 , 1990
29. Robert C. Owens and Paul G. Ambrose ; Clinical Use Of   The Fluoroquinolones , Antibiotic Therapy , part -1 , vol . 84 , pp. 1447 - 1469 , 2000
30. Grossman, R.F., “The role of fluoroquinolones in respiratory tract infections ,” J. Antimicrob. Chemother., vol. 40A ,  pp. 59-62 , 1997
31. R. Wise , D. Honeybourne ; Pharmacokinetic and Pharmacodynamics of Fluoroquinolones in the Respiratory Tract , Eur. Respir. J.,  vol. 14 , pp. 221-229, 1999 
32. Pernet, A. G. In International Telesymposium on Quinolones, P. B. Fernandes, Ed.; J. R. Prous, Barcelona,  pp 417-425, 1989.
33. Scholar, E.M. and Pratt, W., The Antimicrobial Drugs, 2nd ed., Oxford University Press, New York NY ,2000
34. Micheal H. Cynamon and Mary sklaney  ; Gatilfoxacin  and ehtionamide as the foundation for therapy of  Tuberculosis ; Antimicrobial Agents and Chemotherapy,  vol. 47 ,  pp. 2442 - 2444 , 2003
35. Drlica, K. and  Zhao, X.L.,  "DNA gyrase,  topoisomerase IV, and the 4-

quinolones," Mol. Biol. Rev., vol. 61, pp.  377-392 , 1997

36. Shea, M.E. , and Hiasa, H., "Interactions between DNA helicases andfrozen topisomerase IV -quinolone-DNA ternary complexes," J. Biol Chem., vol. 274,   pp. 22747-22754 , 1999
37. Martinez, J.L., Alono, A., Gomez-Gomez, J.M. and Baquero, F., "Quinolone resistance by mutations in chromosomal gyrase genes. Just the tip of the iceberg?," J. Antimicrobial Chemotherapy, vol.42, pp. 683-688 , 1998

About Authors:

Mr. Sandesh R Lodha
Lecturer in Pharmaceutical Chemistry, Maliba Pharmacy College, Gopal Vidyanagar, Bardoli- Mahuwa Road, Tarsadi
Dist – Surat, State – Gujarat, India , Email – sandeshlodha@gmail.com,
Mobile Number - +919998944423

Dr. Akhiles Roy
Professor, Department of Pharmaceutical Chemistry, N.D.M.V.P.S’s College of Pharmacy, Nasik , Dist- Nasik
State – Maharashtra, India, Tel No. - +912532599765
Mobile Number - +919225116716

Dr Shailesh Shah
Professor, Department of Quality Assurance , Maliba Pharmacy College, Gopal Vidyanagar
Bardoli- Mahuwa Road , Tarsadi, Dist – Surat, State – Gujarat, India

Dr. Dinesh Shah
Director, Maliba Pharmacy College, Gopal Vidyanagar, Bardoli- Mahuwa Road, Tarsadi, Dist – Surat State – Gujarat, India

Mr. Bhavin Vyas
Lecturer in Pharmacology, Gopal Vidyanagar, Maliba Pharmacy College, Bardoli- Mahuwa Road , Tarsadi, Dist – Surat, tate – Gujarat, India

Mr. Gajanan Kalyankar
Lecturer in Pharmaceutical Chemistry, Maliba Pharmacy College, Gopal Vidyanagar, Bardoli- Mahuwa Road, Tarsadi, Dist – Surat , State – Gujarat, India

Mr. Shrikant Joshi
Lecturer in Pharmacology, Gopal Vidyanagar, Maliba Pharmacy College, Bardoli- Mahuwa Road, Tarsadi, Dist – Surat, Gujarat , India

Mr. Akshay Koli
Lecturer in Pharmaceutics, Gopal Vidyanagar, Maliba Pharmacy College, Bardoli- Mahuwa Road, Tarsadi, Dist – Surat, Gujarat , India