Quinolone Antibacterial Agents

Table 1. Commercially Significant Quinolone Antibacterial Agents...

Fuhr U, Strobl G, Manaut F, Anders E-M, Sorgel F, Lopez-de-brinas E, et al. Quinolone antibacterial agents relationship between structure and in vitro inhibition of human cytochrome P450 isoform CYP1A2. Mol Pharmacol 1993 43 191-9. 

Over 10000 quinolone antibacterial agents have now been synthesized. Nalidixic acid is regarded as the progenitor of the new quinolones. It has been used for several years as a clinically important drug in the treatment of urinary tract infections. Since its clinical introduction, other 4-quinolone antibacterials have been synthesized, some of which show considerably greater antibacterial potency. Furthermore, this means that many types of bacteria not susceptible to nahdixic acid therapy m be sensihve to the newer derivahves. The most important development was the introduction of a fluorine substituent at C-6, which led to a considerable increase in potency and spectrum of activity compared with nalidixic add. These second-generation quinolones are known as fluoroquinolones, examples of which are ciprofloxacin and norfloxacin (Fig. 5.19). 

According to molecular modeling studies, at the ground state the 6-lluoro analogue of 81 overlaps perfectly with the structure of norfloxacin (a well-established quinolone antibacterial agent) and is predicted to exhibit promising antibacterial activity. 

The synthesis and antibacterial properties of norfloxacin (2a) were described in 1980 [65]. In this key paper in the evolution of quinolone antibacterial agents, a series of 6,7,8-polysubstituted-l-ethyl-l,4-dihydro-4-oxoquinoline-3-carb-oxylic acids (13) was synthesized, employing previously developed quantitative structure-activity relationships (QSAR) for the corresponding 6-, 7- and 8-monosubstituted derivatives versus Escherichia coli. The QSAR analysis... 

Table 6.5. IN VITRO BIOLOGICAL PROPERTIES OF SEVERAL QUINOLONE ANTIBACTERIAL AGENTS [22]...

Thus quinolone antibacterial agents, such as ciprofloxacin CPFX 143 [201], ofloxacin OFLX144 [202],sparfloxacin SPFX145 [203] and trovaflaxin 146 [204] are members of a major class of antibacterial drugs. These fluoroquinolones show broad-spectrum antibacterial activity and are widely used to treat patients with infections, Eq. (58). 

Hemoiytic reactions Rarely, hemolytic reactions have been reported in patients with latent or actual defects in glucose-6-phosphate dehydrogenase activity who take quinolone antibacterial agents, including norfloxacin. 

Itoh, S., Nakayama, S. and Shimada, H. (2002) In vitro photochemical clasto-genicity of quinolone antibacterial agents studied by a chromosomal aberration test with light irradiation. Mutation Research, 517, 113-121. 

MI1 sikl. Soedin., 830 (1989). J. S. Wolfson and D. G Hooper, eds., Quinolone Antibacterial Agents. American Society for Microbiology, Washington, 1989. 

The interaction between the quinolone antibacterials and CYP1A2 has been studied in some depth for enoxacin and pefloxacin. Both compounds have been shown to inhibit CYPlA2-mediated metabolism of caffeine in vitro (49). This in vitro inhibition translated into a twofold decrease in caffeine clearance by pefloxacin and a sixfold decrease in clearance by enoxacin (50). Because pefloxacin undergoes N-demethylation to norfloxacin (51) and norfloxacin is much more potent as an inhibitor than pefloxacin (50), the observed in vivo interaction seen for pefloxacin may, in part, be due to norfloxacin. Many other quinolone antibacterial agents have been investigated for their interaction with theophylline, and ciprofloxacin has also been shown to have notable inhibitory effects (52). 

Fuhr U, Anders EM, Mahr G, et al. Inhibitory potency of quinolone antibacterial agents against cytochrome P450IA2 activity in vivo and in vitro. Antimicrob Agents Chemother 1992 36 942-948. 

Murata M, Tamai I, Kato H, et al. Efflux transport of a new quinolone antibacterial agent, HSR-903, across the blood-brain barrier. J Pharmacol Exp Ther 1999 290 (1) 51—57. 

Kaminsky D, Meltzer RJ. Quinolone antibacterial agents. Oxolinic acid and related compounds. J. Med. Chem.,... 

Chu DTW, Fernandes PB. Recent developments in the field of quinolone antibacterial agents. Adv. Drug Res., 1991,... 

Research on the quinolone antibacterial agents crested a decade ago, as indicated by the fact that Volume 5 in this series described the synthesis of no fewer than 11 drugs in this structural class. The level of activity then, not surprisingly, declined so that only four quinolones were described in Volume 6, which was published in 1999. Two of the three quinolones discussed below were actually prepared before that year their absence in tbe book is due to the circumstance that they had not yet, for some... 

The cyclization to a quinolone (95) in this case is effected with sodium hydride. Treatment of this intermediate with the spiro diamine (96) leads to displacement of fluorine and formation of alkylation product 97. Deprotection by acid-catalyzed cleavage of the t-BOC group flowed by saponification yields the quinolone antibacterial agent 98. ... 

Gemifloxacin is a third generation, oral broad-spectrum, fluorinated quinolone antibacterial agent. It acts by inhibiting DNA synthesis through the inhibition of both DNA gyrase and topoisomerase IV (TOPO TV), which are essential for cellular replication and bacterial growth [7]. It is... 

Shimoda K, Ikeda T, Okawara S, Kato M. Possible relationship between phototoxicity and photodegradation of sitafloxacin, a quinolone antibacterial agent, in the auricular skin of albino mice. Toxicol Sci 2000 56(2) 290-6. 

Interaction of the new quinolone antibacterial agent levo-floxacin with fenbufen in mice. Arzneimittelforschung 1992 43(3A) 406-8. 

Simanjantuk, M.T., Sato, H., Tamai, I., Terasaki, T. and Tsuji, A. Transport of the new quinolone antibacterial agents of lomefloxacin and ofloxacin by rat erythrocytes and its relation to the nicotinic acid transport system. /. Pharmacobio-Dyn., 14, 475-481, 1991. 

Wagai, N and Tawara, K. Important role of oxygen metabolites in quinolone antibacterial agent-induced cutaneous phototoxicity in mice. Arch. Toxicol., 65, 495-499, 1991. 

Maeda, T., Takahashi, K., Ohtsu, N., Oguma, T., Ohnishi, T., Atsumi, R. and Tamai, I. (2007) Identification of influx transporter for the quinolone antibacterial agent levofloxadn. Molecular Pharmacology, 4, 85-94. 

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