H-G Wetzstein1, W Hallenbach. 1. Bayer Animal Health GmbH, Leverkusen, Germany. heinz-georg.wetzstein@bayer.com
Abstract
OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
OBJECTIVES: 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 fluoroquinolonepradofloxacin bears a cyano group at C-8 and it was attempted to define the ranges of activity unfolding upon variation of this moiety. METHODS: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. RESULTS: 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. CONCLUSIONS: 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.