Synthesis and biological activity of 5-amino- and 5-hydroxyquinolones, and the overwhelming influence of the remote N1-substituent in determining the structure-activity relationship

Abstract

A series of 5-amino- and 5-hydroxyquinolone antibacterials substituted at C7 with a select group of common piperazinyl and 3-aminopyrrolidinyl side chains was prepared. These 5-substituted derivatives were compared to the analogous 5-hydrogen compounds for antiinfective activity by using DNA gyrase inhibition, minimum inhibitory concentrations against a variety of bacteria, and in vivo efficacy in the mouse infection model. The influence on the structure-activity relationships of varied substituents at C8 (H, F, Cl) and N1 (ethyl, cyclopropyl, difluorophenyl) was also studied. The results showed that several of the structure-activity conclusions regarding side-chain bulk at C7, the effect of halogen at C8, and the effect of the C5-amino group were greatly influenced by the choice of the N1-substituent. Several outstanding broad spectrum quinolones were identified in this work. In particular, the spectrum and potency of the 7-piperazinyl quinolones could be greatly enhanced by the judicious choice of C5-, C8-, and N1-substituents.

Effects of novel fluoroquinolones on the catalytic activities of eukaryotic topoisomerase II: Influence of the C-8 fluorine group

“…Thus, removal of the C-8 fluorine had little effect on the potency of the quinolone towards the prokaryotic enzyme. A similar observation was made previously by comparing the potencies of the C-8 fluoro derivatives of norfloxacin, perfloxacin, and ciprofloxacin with those of their parent compounds (10,11 (44). This finding suggests that these compounds enhance the levels of DNA breakage primarily by stimulating the forward rate of DNA cleavage.…”

Drug features that contribute to the activity of quinolones against mammalian topoisomerase II and cultured cells: correlation between enhancement of enzyme-mediated DNA cleavage in vitro and cytotoxic potential

“…2A (ii) Ring position C-8. Previous studies suggest that the inclusion of a fluorine group at the C-8 position has little positive effect and in some cases has a detrimental effect on quinolone potency against DNA gyrase (6,7,32). In contrast, the C-8 fluorine enhances activity against Drosophila topoisomerase II -2.5-fold (32).…”

Ethyl 1,4‐dihydro‐4‐oxo‐3‐quinolinecarboxylates by a tandem addition‐elimination‐SNAr reaction

“…Subsequent treatment of 3 with 0.5 equivalents of 2-fluorobenzoyl chloride (2) furnished ethyl 2-(2-fluorobenzoyl)acetate (4) in 85% yield [10]. Condensation of this b-ketoester with N,Ndimethylformamide dimethyl acetal in DMF at 100 C for 30 min then afforded b-enaminone substrate 5 in 97% yield [11].…”

“…The procedure of Domagala et al [10] was modified. In a three-necked roundbottomed flask equipped with an efficient magnetic stirrer (2.5 cm or larger stir bar), 4.17 g (31.6 mmol) of ethyl hydrogen malonate (1) was dissolved in 200 mL of THF and 10 mg of bipyridyl was added as an internal indicator.…”