title: Tuning of antibacterial activity of a cyclopropyl fluoroquinolone by variation of the substituent at position C-8.
abstract: OBJECTIVE
  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.
authors.affiliation: Bayer Animal Health GmbH, Leverkusen, Germany. heinz-georg.wetzstein@bayer.com
authors.forename: H-G
authors.initials: HG
authors.lastname: Wetzstein
authors.forename: W
authors.initials: W
authors.lastname: Hallenbach
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000187:drug effects; D024841:Fluoroquinolones / Q000737:chemistry* / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D009154:Mutation; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; C507250:pradofloxacin