title: Effect of lipophilicity at N-1 on activity of fluoroquinolones against mycobacteria.
abstract: The dramatic increase in drug resistant Mycobacterium tuberculosis has caused a resurgence in research targeted toward these organisms. As part of a systematic study to optimize the quinolone antibacterials against mycobacteria, we have prepared a series of N-1-phenyl-substituted derivatives to explore the effect of increasing lipophilicity on potency at this position. The compounds, synthesized by the modification of a literature procedure, were evaluated for activity against Gram-negative and Gram-positive bacteria, Mycobacterium fortuitum and Mycobacterium smegmatis, and the results correlated with log P, pKa, and other attributes. The activity of the compounds against the rapidly growing, less hazardous organism M. fortuitum was used as a measure of M. tuberculosis activity. The results demonstrate that increasing lipophilic character by itself does not correlate with increased potency against mycobacteria. Rather, intrinsic activity against Gram-negative and/or Gram-positive bacteria is the governing factor for corresponding activity against mycobacteria.
authors.affiliation: Parke-Davis Pharmaceutical Research Division, Warner Lambert Company, Ann Arbor, Michigan 48105, USA.
authors.forename: T E
authors.initials: TE
authors.lastname: Renau
authors.forename: J P
authors.initials: JP
authors.lastname: Sanchez
authors.forename: M A
authors.initials: MA
authors.lastname: Shapiro
authors.forename: J A
authors.initials: JA
authors.lastname: Dever
authors.forename: S J
authors.initials: SJ
authors.lastname: Gracheck
authors.forename: J M
authors.initials: JM
authors.lastname: Domagala
mesh_terms: D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D024841:Fluoroquinolones; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D009161:Mycobacterium / Q000187:drug effects*; D010879:Piperazines / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D010879:Piperazines