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N. Saravana Kumar et al., A Focus on Quinolones and Its Medicinal Importance

REVIEW ARTICLE INTERNATIONL JOURNAL OF NOVEL TRENDS IN PHARMACEUTICAL SCICENCES Available online at www.ijntps.org | ISSN: 2277 - 2782

A Focus on Quinolones and its Medicinal Importance a

b

c

N.Saravana kumar *, D.Dhivya and B.Vijayakumar a

Department of Pharmaceutical Chemistry, Sasikanth Reddy College of Pharmacy, North Rajupalem, Nellore, A P, India. Department of Pharmacognosy, Sasikanth Reddy College of Pharmacy, North Rajupalem, Nellore, A P, India. c Department of Pharmaceutical Chemistry, Sri Venkateswara College of Pharmacy, R.V.S Nagar, Chittoor, A P, India. b

Received for publication, September 14, 2011, and in Revised form, September 19, 2011; Published online in, October 7, 2011

ABSTRACT Quinolones are a very important family of antibacterial agents that are widely prescribed for the treatment of infections in humans. Quinolones comprise a relatively large, growing and most interesting group of antibacterial drugs which have made a major impact on the field of antimicrobial chemotherapy. Since their discovery in the early 1960s, the quinolone group of antibacterials has generated considerable clinical and scientific interest. The bacterial type II topoisomerases, DNA gyrase and topoisomerase IV are validated targets for clinically useful quinolone antimicrobial drugs. A significant limitation to widely utilized quinolone inhibitors is the emergence of drug-resistant bacteria due to an altered DNA gyrase. Antibiotic drug choice will remain difficult in the presence of increasing resistance, but introduction of the new quinolones has created a new and exciting era in antimicrobial chemotherapy. KEY WORDS: Quinolones, antibacterial, topoisomerases, DNA gyrase.

INTRODUCTION Development of antimicrobials for clinical use has been most successful in targeting essential components of 5 general areas of bacterial metabolism: cell wall synthesis, protein synthesis, RNA synthesis, DNA synthesis, and intermediary metabolism (Table 1). The quinolones are a family of synthetic broad-spectrum antibiotics. The term quinolone(s) refers to potent synthetic chemotherapeutic [1] antibacterials . Quinolones comprise a relatively large, growing and most interesting group of antibacterial drugs which have made a major impact on the field of antimicrobial chemotherapy, particularly in the past few [2] years . A group of scientists in the laboratories of the Sterling Company, while pursuing new chemical entities based on the structure of quinine in an effort to expand the armamentarium against malaria, discovered that derivatives of the 1, 8-naphthyridine molecule possessed antibacterial activity. By 1962, George Lesher and colleagues had [3] developed Nalidixic acid (1) . This was the first clinically useful quinolone in the series, and by 1964 it was available in the UK for the treatment of urinary tract infections. This narrow clinical indication was a consequence of two factors: the poor serum and tissue concentrations achieved after oral administration, and the limited spectrum of activity,

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[4]

restricted primarily to the Enterobacteriaceae . Thereafter, novel compounds of this family, such as pipemidic acid and oxolinic acid, were synthesized and introduced into clinical practice, although the clinical indication for these quinolones still remained only for UTIs. The addition of a fluorine atom at position 6 of the quinolone molecules greatly enhanced their activity, facilitating their usage beyond UTIs. C2 H5 H 3C

N

N OH O

O

1 During the 1980s, a great number of fluoroquinolones were developed. These agents showed potent activity against Gram-negative bacteria, but not against the Gram-positive bacteria or anaerobes. In the 1990s, further alterations of the quinolones resulted in the To whom correspondence should be addressed: Ms. N. Saravana Kumar,

E-mail: njk.saravana@gmail.com Phone: +918106105188

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N. Saravana Kumar et al., A Focus on Quinolones and Its Medicinal Importance

discovery of novel compounds that not only showed potent activity against Gram-negative bacteria but also against the [5] Gram-positives . Fluoroquinolones as a class is now a days one of the frequently prescribed class of antibacterial. Fluoroquinolones have gained stupendous importance during the last two decades because of their potent antibacterial activity against wide varieties of gram-positive and gram-negative pathogenic bacteria with minimum toxic side-effects and somewhat different mechanism of action than other available antibacterial drugs. To date, many fluoroquinolone antibacterial agents have been introduced into clinical use (Table 2) with significant improvement in antibacterial spectrum and activity. A vast array of fluoroquinolones having excellent broad-spectrum activity forms an invaluable part of the present anti-infective armory of the clinicians. A number of these compounds are today's blockbusters of the antibacterial market due to their therapeutic efficacy and tolerable side-effects even, 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 [6] community sectors to treat a broad range of infection Table 1. Bacterial targets of antimicrobial agents. BACTERIAL TARGET Cell wall synthesis Protein synthesis

RNA synthesis DNA synthesis Intermediary metabolism

ANTIMICROBIAL AGENT β-Lactam antibiotics Glycopeptides Aminoglycosides, Macrolides, Lincosamides, Ketolides, Streptogramins, Tetracyclines, Chloramphenicol Oxazolidinones Rifamycins Coumarins, Naphthyridines, Quinolones, 2-Pyridones Sulfonamides, Trimethoprim

Clinical uses The fluoroquinolones have been used to treat a great variety of infections (Table 4), including gonococcal infections, osteomyelitis, enteric infections or respiratory [9-11] tract infections, and as prophylaxis in neutropenic patients, surgery or to prevent spontaneous bacterial [10,12] . peritonitis in cirrhotic patients, among others Moreover, quinolones, along with other antibacterial agents, have been extensively used in veterinary practice,

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either for medical reasons or as growth promoters. The list of fluroquinolones with their indication, dose and duration of therapy were shown in table 4.

BIOLOGICAL TARGET Fluoroquinolones are a clinically important class of antibacterial drugs that target the type II A topoisomerases DNA gyrase and topoisomerase IV (Fig 1) , two highly homologous enzymes that play essential roles in bacterial [13-17] DNA replication . DNA gyrase is a heterotetrameric protein consisting of two GyrA subunits and two GyrB subunits (A2B2) encoded by the gyrA and gyrB genes, respectively. The GyrA subunit mediates the enzymecatalyzed DNA breakage-reunion reaction and contains the active-site tyrosine that forms a covalent complex with the 5'-labeled ends of the transiently cleaved DNA duplex. The GyrB subunit contains an ATPase activity which facilitates the DNA strand passing reaction of DNA gyrase. Topoisomerase IV, a paralogue of DNA gyrase, is also a heterotetramer, consisting of two ParC and two ParE subunits which are homologues of the GyrA and GyrB subunits of DNA gyrase, respectively. Fluoroquinolones interact with the DNA breakage-reunion subunit of DNA gyrase and topoisomerase IV, leading to the stabilization of the covalent topoisomerase/DNA cleavable complex which [18] blocks DNA replication . How do quinolones destroy bacteria without hurting our cells? There are many different classes of antibiotics each exerting a different type of inhibitory effect that specifically impacts bacteria. Bacterial cells are prokaryotic; primitive cells that differ significantly from humans’ eukaryotic cells. Quinolones exert their bacteriocidal effect by interfering with a bacterium’s ability to make DNA (replication). Many quinolone antibiotics belong to a subgroup called fluoroquinolones, which have a fluoro functional group associated with the molecule. Both terms are therefore used to describe antibiotics in this class.

Fig.1 Inhibition of DNA gyrase and Topoisomerase IV by Fluoroquinolone

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N. Saravana Kumar et al., A Focus on Quinolones and Its Medicinal Importance

Table 2. Structural Formulas of Selected Quinolones and Fluoroquinolones R R

8

3

x

7

1

1

N

2

6

R

2

5

4

O

Compound Name

Nalidixic acid

Cinoxacin

R

1

R

-C 2 H 5

R

-H

3

X

-N-

-CH 3

[Fused dioxolo ring]

-C 2 H5

Norfloxacin

O

2

-C 2 H5

*

OH

3

Ciprofloxacin

-CH-

-F

N

NH

-CH-

-F

N

NH

-CH-

-F

N

NH

-CH-

8

C

O

Ofloxacin

CH3 Sparfloxacin

CH3 F

**

-F

N

C

NH

CH3 F Lomefloxacin

-C 2 H5

-F

N

NH

C

CH3 F Fleroxacin

-CH 2 -CH 2 -F

-F

N

N

CH3

C

Perfloxacin

-C 2 H 5

-F

N

N

CH3

-CH-

Levofloxacin

CH3

O

-F

(x)

CH3

O N

N

CH3

(N 1 )

C

(N 1 )

F Trovafloxacin

Intl.J.Novel.Tr.Pharm.Sci

F

-F

N

NH2

-N-

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N. Saravana Kumar et al., A Focus on Quinolones and Its Medicinal Importance

Table 2. (continued) Structural Formulas of Selected Quinolones and Fluoroquinolones R R

8

3

N1

x

7

1

2

6

R

OH

2

5

4

O

Compound Name

R

1

R

3

O

2

R

3

X CH3 OCH 3

-F

Gatifloxacin

N

C

NH

OCH 3 -F

Moxifloxacin

N

C N H

*An N replaces C-2 in the basic ring structure of Cinoxacin.

Fused dioxolo

**An –NH2 group is attached to the C-5 in the basic ring structure of Sparfloxacin.

O C O

Table 3 Classification on the Basis of Spectrum of Activity

Quinolone generations First generation Nalidixic Acid ( NegGram) Cinoxacin Second generation Class I Lomeflaxcin Norfloxacin Enoxacin

Class II Ofloxacin Ciprofloxacin

Third generation Levofloxacin Sparfloxacin Gatifloxacin Moxifloxacin Fourth generation

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[7, 8]

Microbiological activity

Administration and characteristics

Indications

Enterobacteriaceae

Oral administration , low serum and tissue drug concentrations, narrow gram-negative coverage

uncomplicated urinary tract infections , not for use in systemic infections

Enterobacteriaceae

Oral administration , low serum and tissue drug concentrations , improved gram negative coverage compared to first generation quinolones , limited gram positive coverage

uncomplicated urinary tract infections , Not for use in systemic infections

Enterobacteriaceae , atypical pathogens ; Pseudomonas aeruginosa (ciprofloxacin only)

Oral and intravenous administration, higher serum , tissue and intracellular drug concentrations compared with class I agents coverage of atypical pathogens

Complicated urinary tract and catheter-related infections, Gastroenteritis with severe diarrhea , Prostatitis , Nosocomial infections , STD's

Enterobacteriaceae , atypical pathogens , streptococci

Oral and intravenous administration , similar to class II second generation quinolones but with modest streptococcal coverage

Similar indications as for second generation quinolones ,community acquired pneumonia in hospitalized patients.

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N. Saravana Kumar et al., A Focus on Quinolones and Its Medicinal Importance

Trovafloxacin

Enterobacteriaceae , atypical pathogens ,Pseudomonas aeruginosa , methicillinsusceptible Staphylococcus aureus, streptococci, anaerobes

Oral and intravenous administration, similar to third generation quinolones but with improved gram-positive coverage and added anaerobic coverage

Consider for treatment of intraabdominal infections .

Table 4 Drug, Indication, Dose, Duration of therapy chart for some Fluoroquinolones Drug Ciprofloxacin

Indication Uncomplicated UTI Complicated UTI ; Acute pyelonephritis Uncomplicated N gonorrhea AECB , CAP Acute prostatitis Infectious diarrhoea ; Typhoid Fever Uncomplicated UTI Uncomplicated N gonorrhea Complicated UTI ; Acute pyelonephritis, AECB , CAP Uncomplicated UTI ; Acute pyelonephritis AECB, CAP Uncomplicated and complicated UTI ; Acute pyelonephritis Acute prostatitis Uncomplicated and complicated UTI ; Acute pyelonephritis; AECB AECB , CAP

Gatifloxacin

Levofloxacin Norfloxacin

Lomefloxacin Sparfloxacin Moxifloxacin Ofloxacin

PO dose ( mg ) 100 250-500 500 500-750 500 500 400 400 400

Interval BID BID 1-dose BID BID BID QD 1-dose QD

Duration ( days ) 3 7-14 1-dose 10-14 14-28 3-5 3 1-dose 7-14

250 500 400

QD QD BID

10 7- 14 3-10

400 400

BID QD

14-28 3-14

400 x 1 , then 200 400 200

QD

10

AECB , CAP QD 5-10 Uncomplicated and complicated UTI ; BID 3-10 Chlamydia Uncomplicated N gonorrhea 400 1-dose 1-dose AECB , CAP 400 BID 7-10 CAP = community acquired pneumonia AECB = acute exacerbations of chronic bronchitis UTI = urinary tract infections

Table 5. Severity of Adverse Effects Associated with Fluoroquinolones Quinolones

Gastrointestinal reactions

CNS Effects

Ofloxacin Levofloxacin Norfloxacin Ciprofloxacin Pefloxacin Tosufloxacin Trovafloxacin Temafloxacin Moxifloxacin

+ ++ + + ++ ++ +++

+ + ++ ++ ++++ ++++ + +

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Photo toxicity ++ +

Liver toxicity

Hypogly caemia

Tendinitis

+++ -

+++ +++ -

+++ -

Cardio toxicity -

Haemolitic syndrome +++ ++++ -

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N. Saravana Kumar et al., A Focus on Quinolones and Its Medicinal Importance

Lomefloxacin Fleroxacin Sparfloxacin Clinafloxacin Grepafloxacin

+++ +++ ++++

++++ ++++ + ++++ +

++++ ++++ ++++ ++++ -

-

Quinolones are bacteriocidal drugs, meaning that they kill bacteria. These antibiotic drugs inhibit the bacterial DNA gyrase enzyme which is necessary for DNA replication. Since a copy of DNA must be made each time a cell divides, interfering with replication makes it difficult for bacteria to multiply. How DNA is packaged is very different in bacteria as opposed to eukaryotes. Bacteria super coil DNA using DNA gyrase, whereas eukaryotes coil DNA around histone proteins. Because quinolones specifically target DNA [19] gyrase, they do not interfere with human DNA .

STRUCTURE-ACTIVITY RELATIONSHIPS The structure of quinolone pharmacophore was shown in Fig. 3 The figure shows the core molecule and the positions at which key changes are engineered. Some of these molecular substitutions should not be altered as they would interface with or reduce markedly the basic mode of action of the drug. These are positions 2, 3 and 4; at position 2, a hydrogen moiety is optimal - any larger molecular additions may create a steric hindrance at the adjacent positions 3 and 4 which must be a carboxyl group and oxygen molecule, respectively. Binding to the DNA bases occurs at these positions, which are then made available for new hydrogen binding partners by the action of the enzyme, DNA gyrase. The moiety at position 6 should be small, and a fluorine atom is optimal as it confers between five- and 100-fold greater potency than any other potential halogen moiety. The four other positions can [4] receive a wide range of potential substituents . SAR studies have enabled the recognition of features that lead to specific changes, as summarised below:-

R R

8

7 7

1

1

x

N

R

2

++ -

+++ +++ -

+++ +++

-

It was realised that a cyclopropyl moiety (e.g., as seen in ciprofloxacin and sparfloxacin) at this point conferred significant activity against gram-negative bacteria. The groups 2,4-difluorophenyl (temafloxacin)and t-butyl (BMY 40062) are slightly less potent; however, the 2,4difluorophenyl group heightens activity against anaerobes [20] . Position 5 Considerable changes have been concentrated at this position in an effort to improve the activity of the fluoroquinolones against gram-positive bacteria. The most advanced compounds that carry significant changes at position 5 are sparfloxacin and PD 124816, both of which carry an -NH2 moiety, whereas OPC 17116 (grepafloxacin) [4] possesses a -CH3 molecule . Position 7 This is one of the most influential points on the molecule and, almost without exception, the possession of a five or six-membered nitrogen heterocycle at this position has improved a molecule’s activity and pharmacokinetic profile. The most popular heterocycles employed at position 7 are aminopyrrolidines and piperazines. Antibacterial agents that contain an aminopyrrolidine moiety [21] are tosufloxacin, clinafloxacin, Du6859a, Bay 3118 . In contrast, the piperazine substituent is found on ciprofloxacin, lomefloxacin, temafloxacin, sparfloxacin and BMY 40062. The former moiety tends to confer better activity against gram-positive bacteria, whereas piperazine [20] offers improved activity against gram-negative bacteria . Substitution with an alkyl moiety will improve gram positive potency and lengthen the serum half-life; this type of change has been employed in lomefloxacin, sparfloxacin and several other quinolones now under development.

2 6

F

4

5

R

5

OH

3

O

O

Fig 2. The quinolone pharmacophore Position 1

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Position 8 Various substituents at this position have led to marked improvements in activity, particularly against anaerobic bacteria; the most useful groups employed on this position are CF, CCl and COMe.In addition to the role that certain moieties may play in enhancing activity against specific groups of bacteria and altering the pharmacokinetic properties of a drug, these chemical

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N. Saravana Kumar et al., A Focus on Quinolones and Its Medicinal Importance

modifications also play a significant role in the specific [4] interaction of these compounds with man .

8.

ADVERSE REACTIONS The most common adverse experience reported for all quinolones involve the gastro-intestinal tract, skin and CNS. Of the gastrointestinal events, nausea and vomiting are the most common. CNS reactions vary in severity and include dizziness, convulsions and psychoses [22-24] . Occasionally major events occur, which lead to significant tolerability problems. Phototoxicity, cardiotoxicity, arthropathy and tendinitis have also been [25-28] observed in some patients (Table 5 ) .

9.

10. 11. 12.

13. Conclusion Without doubt, the newer quinolones have very attractive properties, combining high potency, a broader spectrum of activity, better bioavailability, oral and intravenous formulations, high serum levels, a large volume of distribution indicating higher concentrations in tissues and a potentially low incidence of side-effects. From a clinical perspective, the main problem with the quinolones is the accumulation of resistance mutations by target organisms. The recent demonstration that bacteria contain two targets for the fluoroquinolones raises the hope that new quinolones can be found that will effectively attack both targets and thus drastically reduce the probability of development of clinical resistance. Our present knowledge in the topic provides wide scope for developing newer quinolones to inhibit the highly resistant bacteria. Therefore, we are optimistic about being able to find new, more effective quinolones.

14. 15. 16. 17. 18.

19.

20. 21.

References 1. 2.

3.

4. 5. 6.

7.

Nelson JM, Chiller TM, Powers JH, Angulo FJ. Clin. Infect. Dis, 2007, 44 (7): 977–80. Saeed Emami, Abbas Shafiee and Alireza Foroumadi. Iranian Journal of Pharmaceutical Research, 2005, 3, 123-136. Lesher GY, Froelich ED, Gruet MD, Bailey JH, Brundage RP. J Med Pharm Chem, 1962, 5, 10631068. G. S. Tillotson. J. Med. Microbiol, 1996, 44, 320-324. Joaquim Ruiz, Journal of Antimicrobial Chemotherapy, 2003, 51, 1109–1117. Akhiles Roy, S. M. Sardar, B.U.Salve, D.D.Rishipathak. International Journal of ChemTech Research, 2007;1: 35-46 Andriole, V. T. Drugs, 1999, 58:1.

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