Quinolone antibacterial spectrum

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). 

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). 

Introduction of the first fluorinated quinolone, norfloxacin [nor FLOX a sin], has been rapidly followed by new members of this class. These agents are totally synthetic and are closely related structurally to an earlier quinolone, nalidixic acid [nal i DIX ik]. The principal member of this group is ciprofloxacin [sip ro FLOX a sin], which has the widest clinical application. Other antibiotics in this group available in the United States are primarily employed to treat urinary infections (Figure 32.1). It seems likely that the size of this class of antibiotics will increase due to its wide antibacterial spectrum, favorable pharmacokinetic properties and relative lack of adverse reactions. Unfortunately, their overuse has already led to the emergence of resistant strains resulting in limitations to their clinical usefulness. 

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... 

There are several methods of preparation of antibacterial quinolones, drugs widely used in the therapy of various bacterial diseases. The most general method is based on the nucleophilic cyclization of 2-halobenzoyl derivatives 402, leading to the key intermediates 403. The methodology is exemplified in Scheme 63 by the synthesis of a broad-spectrum drug ciprofloxacin... 

Since the introduction of nalidixic acid in 1963, structural modifications on the quinolones have been performed to improve either the antibacterial efficacy or pharmacokinetic/toxicologic profiles of these compounds. The newest quinolones possess broad-spectrum activity, favorable pharmacokinetic/toxicologic profiles, and potency against bacterial strains that are resistant to older generations of quinolones. This section describes the synthetic procedures for the new generation of quinolones that were studied during the 1995-2005 period. 

Very much the same strategy is used to synthesize a quinolone that contains an additional fused ring. This agent features a broad-spectrum antibacterial activity in spite of the lack of a nitrogen substituent at position 7. It is of note in this case... 

A large number of tricyclic fluoroquinolones, in which the 1,3-thiazetidine moiety is fused to the quinolone, have been reported as good antibacterial agents, for example, prulifloxacin, displaying a broad spectrum with low toxicity. 

Pyridyl quinolone carboxylic acids, (V), and 7-piperazine quinazolin-2,4-dione derivatives, (VI), prepared by Park (5) and Domagala (6), respectively, exhibited broad-spectrum antibacterial activity with reduced cytotoxicity. 

Enoxadn, USP. l-Ethyl-6-fluoro-l.4-dihydro-4-oxo-7-(I-piperazinyI)-I,8-naphthyridine-3-carboxylic acid (Pene-irex) is a quinolone with broad-spectrum antibacterial activity that is used primarily for the treaimenl of urinary tract infections and. sexually transmitted diseases. Enoxacin has been approved for the treatment of uncomplicated gonococcal urethritis and has also been shown to be effective in chancroid caused by Haemophilus ducreyi. A single 400-mg dose is used for these indications. Enoxacin is also approved for the treatment of acute (uncomplicated) and chronic (complicated) urinary tract infections. 

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