In another expansion of quinolone SAR, a series of antibacterial quinolizin-4-ones has been reported [159,160]. Generically referred to as 2-pyridones, these agents display a reorganized quinolone nucleus in which the nitrogen at the 1-position has been moved to the ring junction (see ABT-719, A-170568, Figure 9). These agents still serve to inhibit the gyrase and topoisomerase IV enzymes, however, despite this substantial structural modification [161]. The SAR of this series parallels that of the quinolones in large part, with the fluorine atom providing heightened potency against both Gram-positive and Gram-negative organisms, and a cyclopropane at the position corresponding to N-1 of the quinolone nucleus giving better activity than an ethyl group. As in the case of the quinolones, a distal amine seems to be required for in vivo activity. ABT-719, the most intensively examined member of this series, is an analogue of an N-1 cyclopropyl quinolone, where the cyclopropane is now bonded to a carbon atom. A methyl group at the position corresponding to C-8 of the quinolone skeleton was found to be useful in this case as well, where it proved superior to fluoro, chloro, and methoxy substituents. ABT-719 exhibits Gram-positive activity superior to that of cli-nafloxacin. Versus the Enterobacteriaceae, it was similar to or slightly better than ciprofloxacin and clinafloxacin, whereas P. aeruginosa activity was improved fourfold over ciprofloxacin. Activity against anaerobes was similar to that of clinafloxacin, and ABT-719 exhibited more potent activity than clinafloxacin against quinolone-resistant S. aureus and P. aeruginosa [162,163]. In animal models of infection, ABT-719 gave improved efficacy over ciprofloxacin against Gram-positive organisms, with Gram-negative efficacy similar to ciprofloxacin [164]. A more recent entry is A-170568, which bears a sidechain closely related to that of sitafloxacin [165,166]. While exhibiting less potent activity against P aeruginosa than ABT-719, A-170568 retains potent activity against ciprofloxacin-resistant Gram-positive organisms, and excellent activity against B. fragilis. Importantly, this change in the sidechain structure results in a substantial decrease in the activity against the human topoisomerase II enzyme, and an increase in the murine intraperitoneal LD50 compared to ABT-719. While the analogue lacking the methyl on the amino group was a slightly more potent antibacterial than A-170568, it did not exhibit the same improvement in LD50 and topoisomerase II activities [165].

Alteration of Primary Enzymatic Target

Much research has been carried out to determine the primary target enzymes for fluoroquinolones, which have been found to vary between different organisms and quinolones (see section on "DNA Gyrase versus Topoisomerase IV"). Interest is high in obtaining agents with equivalent activity against both gyrase and topoisomerase IV, in the hope of minimizing the selection of resistant organisms. Sitafloxacin has been shown to have this desirable dual activity against enzymes from S. pneumoniae [167,168]. Some divergence in primary target in S. pneumo-niae has been observed, with sparfloxacin and gatifloxacin reported to target gyrase, and a number of other quinolones having topoisomerase IV as primary target [169] (see [167] and the section on "DNA Gyrase versus Topoisomerase IV," however, for some inconsistencies with these conclusions).

The advanced stage quinolones that have been studied are disparate enough in structure that the SAR for enzyme selectivity is difficult to discern. One paper reports that the primary target of ciprofloxacin in S. pneumoniae can be converted from topoisomerase IV to gyrase through a single chemical modification [170]: addition of a 4-aminobenzenesulfonyl group to the distal nitrogen (compound 2, Figure 9).4 The alteration in target specificity was confirmed through examination of MIC against defined mutants, selection of first-step mutants and differential activity of ciprofloxacin and compound 2 against isolated topoisomerase IV and gyrase from S. pneumoniae [170]. Thus, the identity of the primary enzyme target can be altered by molecular modification solely at the C-7 substituent. Additional efforts will certainly be applied to adjust the enzymatic activity of new analogues, such that a balance of gyrase and topoisomerase IV activity can be reached.

As can be seen from this discussion, structural innovations in the quinolone area have provided agents substantially improved over ciprofloxacin, in terms of both in vitro potency and in vivo properties. These intriguing expansions in quinolone SAR suggest that continued research may yield further therapeutic advances [171].

Throughout the discovery and development of improved fluoroquinolone agents, assessment of the potency of various analogues against DNA gyrase and,

4It was shown that a sulfonamide mechanism does not contribute to the antibacterial action of compound 2 [170].

more recently, topoisomerase IV, has assisted in optimization of antibacterial activity. The following section describes mechanistic discoveries involving the action of quinolones against both DNA gyrase and topoisomerase IV.

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