Bayer Animal Health GmbH, Leverkusen, Germany.
J Antimicrob Chemother. 2011 Dec;66(12):2801-8. doi: 10.1093/jac/dkr372. Epub 2011 Sep 21.
If substituted at position C-8 by a methoxy group, fluoroquinolones possess antibacterial efficacy considerably improved over that of C-H analogues. The new veterinary fluoroquinolone pradofloxacin bears a cyano group at C-8 and it was attempted to define the ranges of activity unfolding upon variation of this moiety.
Pradofloxacin and six analogues were subjected to MIC and mutant prevention concentration (MPC) analysis; we determined comparative activities against one wild-type and two isogenic first-step fluoroquinolone-resistant variants each of Escherichia coli and Staphylococcus aureus. Ciprofloxacin, enrofloxacin and its 8-CN analogue, the R,R-pyrrolidinopiperidine enantiomer of pradofloxacin as well as the 8-OH congener of pradofloxacin served as references.
MICs were of limited utility in resolving differences in antibacterial activity. Regarding MPCs, E. coli was inhibited most effectively by ciprofloxacin. However, pradofloxacin and analogues bearing Cl or F closely matched that activity. MPCs of O-alkyl and the R,R-pyrrolidinopiperidine-substituted compounds indicated lower activities, while the 8-OH metabolite, essentially, had lost activity. Replacement of 8-H by CN, resulting in up to 7-fold reduced MPCs, was a prerequisite for high activity against the wild-type strains and first-step fluoroquinolone-resistant variants. Narrowed mutant selection windows, observed for both variants of E. coli and wild-type S. aureus, indicated an improved potential of pradofloxacin for restricting the selection of clones with reduced susceptibility.
Substitution of hydrogen at position C-8 of an analogue of pradofloxacin by CN provided for MPCs lower than those of 8-O-CH(3) and almost similar to C-8-halogenated compounds, while alkoxy substituents caused reduced activity and hydroxylation resulted in inactivation. Efficacy was co-dependent on the amine moiety located at C-7.
如果氟喹诺酮类化合物在 C-8 位被甲氧基取代，其抗菌效果将大大优于 C-H 类似物。新型兽医氟喹诺酮类药物普拉洛芬在 C-8 位带有氰基，人们试图确定该部分变化所产生的活性范围。
对普拉洛芬和 6 种类似物进行 MIC 和突变预防浓度（MPC）分析；我们确定了对大肠杆菌和金黄色葡萄球菌的每个野生型和两个同源的第一步氟喹诺酮耐药变异体的比较活性。环丙沙星、恩诺沙星及其 8-CN 类似物、普拉洛芬的 R,R-吡咯烷哌啶对映体以及普拉洛芬的 8-OH 同系物均作为参考。
MIC 在解决抗菌活性差异方面的作用有限。关于 MPC，大肠杆菌最有效地被环丙沙星抑制。然而，普拉洛芬和带有 Cl 或 F 的类似物紧密匹配该活性。O-烷基和 R,R-吡咯烷哌啶取代化合物的 MPC 表明活性较低，而 8-OH 代谢物基本上已经失去活性。8-H 被 CN 取代，导致 MPC 降低了 7 倍，这是对野生型菌株和第一步氟喹诺酮耐药变异体具有高活性的前提。观察到大肠杆菌的两种变异体和野生型金黄色葡萄球菌的突变选择窗变窄，表明普拉洛芬在限制具有降低敏感性的克隆选择方面具有更大的潜力。
在普拉洛芬类似物的 C-8 位用 CN 取代氢提供了比 8-O-CH（3）和几乎类似于 C-8-卤代化合物更低的 MPC，而烷氧基取代基导致活性降低，而羟基化导致失活。疗效与位于 C-7 的胺基部分密切相关。
