Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 66 No. 6 pp. 587ñ604, 2009 ISSN 0001-6837 Polish Pharmaceutical Society REVIEV FLUOROQUINOLONE ANTIBACTERIALS: A REVIEW ON CHEMISTRY, MICROBIOLOGY AND THERAPEUTIC PROSPECTS PRABODH CHANDER SHARMA1*, ANKIT JAIN1 and SANDEEP JAIN2 1 Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra-136119, India 2 Department of Pharmaceutical Sciences, Guru Jambheshwar University of Science and Technology, Hisar-125001, India Abstract: Fluoroquinolones are one of the most promising and vigorously pursued areas of contemporary anti- infective chemotherapy depicting broad spectrum and potent activity. They have a relatively simple molecular nucleus, which is amenable to many structural modifications. These agents have several favorable properties such as excellent bioavailability, good tissue penetrability and a relatively low incidence of adverse and toxic effects. They have been found effective in treatment of various infectious diseases. This paper is an attempt to review the therapeutic prospects of fluoroquinolone antibacterials with an updated account on their develop- ment and usage. Keywords: fluoroquinolone, antibacterial, ciprofloxacin, therapeutic Antiinfective chemotherapy is the science of piratory tract infections (RTI), sexually transmitted administering chemical agents to treat infectious diseases (STD) and skin infections (5, 6). They are diseases. This practice has proven to be one of the primarily used against urinary tract infections and most successful of all pharmaceutical studies (1). are also clinically useful against prostatitis, infec- Historically, the use of anti-infective agents can be tions of skin and bones and penicillin resistant sex- credited with saving more human lives than any ually transmitted diseases (4). These agents are also other area of medicinal therapy discovered to date. employed against bacterial enteric infections, pro- Antibacterial chemotherapy accounts for the major- phylaxis in the immuno compromised neutropenic ity of antiinfective agents in comparison to antifun- host. New quinolones provide a valid alternative gal, antiviral and antiparasitic agents. It is a highly antibacterial therapy, especially in areas where the valued medical science, which has shaped modern prevalence of pencillin resistant and macrolide humanity in a phenomenal fashion (1, 2). Ehrlich resistant organisms exist (7). successfully developed the first purely synthetic rev- olutionary antimicrobial drug salvarsan in 1910 (2). Historical background Afterwards, beta-lactam antibiotic penicillins and The first clinically useful quinolone was sulfonamides have been the most promising or dom- naldixic acid, discovered by Lesher and co-workers inating drugs in clinical usage (3). in 1962, which was generated from chloroquine, an Quinolones and fluoroquinolones are a rela- antimalarial agent (3). It was active against some tively new class of synthetic antibiotics with potent Gram negative bacteria and had limited usefulness bactericidal, broad spectrum activity against many because of its high protein binding (approximately clinically important pathogens which are responsi- 90%) and little half life (about 1.5 h) (8). ble for variety of infections including urinary tract Unfortunately, bacteria could develop a rapid resist- infections (UTI), gastrointestinal infections (4), res- ance to this agent (9, 10). * Corresponding author: e-mail: [email protected][email protected]. 587 588 PRABODH CHANDER SHARMA et al. quinolones have been patented and are still used today, including norfloxacin (1978), pefloxacin (1979), enoxacin (1980), fleroxacin (1981), ciprofloxacin (1981) and ofloxacin (1982) (3). An advantage of these compounds over previous ones is their broad spectrum. A big revolution was made in 1980ís when an analog of naldixic acid, enoxacin was derived with significantly increased spectrum of In 1968, Kaminsky and Melfezer discovered an activity against Gram negative or Gram positive oxolinic acid, which was lately approved by the bacteria (2). United States Food and Drug Administration The most successful and widely used fluoro- (USFDA) (9). Since then, extensive efforts has been quinolone, ciprofloxacin was marketed in 1986, and undertaken for the development and to derive an since then the value of fluoroquinolones for the array of significantly active drugs of this class. treatment of a wide range of infections have become Molecular modification for the lead optimization by widely recognized (3, 11). This class of compounds bioisosteric replacements, homologation of side has enhanced pharmacokinetic properties as well as chain or branching of side chain, stereochemistry extensive and potent activities against various para- and other useful techniques of analogs design and sites, bacteria and mycobacteria, including resistant development of fluoroquinolones have given rise to strains as compared to previously existing bacterici- agents with broad spectrum activity and minimum dal drugs (11, 12). toxic or side effects. Development of new antibi- otics has been achieved from derivatives of known Classification antimicrobial agents or by identification of novel Fluoroquinolones are classified (Table 1) on agents active against previously unexploited targets. the basis of their spectrum of activity and their phar- The development has been focused on the following macokinetic profile (13). aspects (3): Increasing activity against resistant strains of Structure-activity relationships (SAR) microbes, anaerobes and atypical organisms. Essential structural features Reducing rate of emergence of resistance. All clinically important compounds of fluoro- Improving pharmacokinetics and pharmacody- quinolone class are synthetic fluorinated analogues namic profile. of naldixic acid, a 1,8-naphthyridine and possess a Targeted towards selectivity of drugs. 4-quinolone nucleus (14). Flumequine was the first fluoroquinolone In general, pharmacophore required for signifi- which was patented in 1973, after that many fluoro- cant antibacterial activity is 4-pyridone-3-carboxylic Table 1. Classification of fluoroquinolones Generation Drug Characteristic features Naldixic acid Active against some Gram negative bacteria. First Oxolinic acid Highly protein bound drugs. Pipemidic acid Short half life. Norfloxacin Enoxacin Protein binding (50%). Second Ciprofloxacin Longer half life than previous agents. Ofloxacin Improved activity against Gram negative bacteria. Lomefloxacin Temafloxacin Third Sparafloxacin Active against Gram negative bacteria. Grepafloxacin Also active against Gram positive bacteria. Clinafloxacin Fourth Trovafloxacin Show extended activity against both strains of bacteria. Moxifloxacin Active against anaerobes and atypical bacteria. Gatifloxacin Fluoroquinolone antibacterials: a reviev on chemistry... 589 acid with a ring at 5 or 6 position (Fig. 1). Now con- siderable information is available about the effects of modifications on nucleus. Although various alter- ations were done to improve antibacterial activity (3, 4, 15-31), two major pathways of lead optimization of original 1,8-naphthyridine nucleus were pursued. Both the strategies are based on modification of 6- fluoro and 7-piperazinyl quinolone (6). It is pertinent to mention here that a similarity Figure 1. Required pharmacophore of quinolone is seen in many fluoroquinolones with beta lactams, wherein a reciprocal relationship is seen in both the classes where an increase in Gram positive activity is associated with a decrease in Gram negative activ- ity (3). The first route of lead optimization involved replacement of nitrogen atom by carbon atom at position-8, as well as other side chain modifications, Figure 2. Basic quinolone nucleus for SAR resulting in fluoroquinolones such as 1-cyclopropyl (ciprofloxacin) and 1,8-cyclo compounds such as potency of the drug. The earlier compounds such as ofloxacin and levofloxacin (6). Additional molecu- naldixic acid, pipemidic acid, norfloxacin, lar substitution at 6-fluoro, 7-piperazinyl yielded enofloxacin, cinoxacin, rosoxacin etc. had an ethyl second generation agents with improved activity and group as side chain at the nitrogen atom (9). So the pharmacokinetic profile, such as sparfloxacin and optimal substituent at position one appeared to be clinafolxacin (6, 32). These compounds demonstrat- ethyl, but cyclopropyl and difluorophenyl have ed greatly improved activity against many Gram resulted in increased potency (3). Addition of some positive species without compromising on their small group at cyclopropyl, as fluorine in case of activity against Gram negative bacteria, contrary to fleroxacin, results in overall improved activity the earlier agents of this class (3). against Gram positive bacteria. Replacement of cyclopropyl group of ciprofloxacin by an oxetane (compound A) had increased Gram positive activity relative to ciprofloxacin. Connecting the methoxy or hydroxy group at carbon-8 atom to a dimethylamino group at nitrogen-1 atom (compound B) displayed superior in vitro and in vivo antibacterial activity as compared to ofloxacin and ciprofloxacin in addition to having good bioavailability (94%) and half life of 4.6 h (6). The second major route of chemical modifica- tions retained the naphthyridine core, yielding agents such as enoxacin and tosufloxacin (32). The 7-azabicyclo evolutionary modification lead to third generation molecule of trovafloxacin, which showed, increased spectrum of antibacterial activity and also