title: Inhibitory activity on DNA gyrase and intracellular accumulation of quinolones: structure-activity relationship of Q-35 analogs.
abstract: Q-35, 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3- methylaminopiperidine-1-yl)-4-oxyquinoline-3-carboxylic acid, has excellent activity against gram-positive bacteria and inhibits S. aureus gyrase at concentrations more than 10-fold lower than those of other quinolones. In this paper, the effect of the C-7 and C-8 substituents of Q-35 on the inhibitory activity of gyrase purified from S. aureus, M. luteus, E. coli, and P. aeruginosa are described. In addition, intracellular accumulation of Q-35 was examined. The 50% inhibitory concentrations (IC50) of Q-35, 8-fluoro- Q-35, and 8-hydro-Q-35 on DNA gyrase purified from S. aureus were 2.5, 7.8, and 68 micrograms/ml, respectively. The IC50 on gyrase from P. aeruginosa were 11, 5.2, and 17 micrograms/ml, respectively. It is concluded that the introduction of a methoxy group into the 8 position of the quinolone leads to greater antibacterial activity against gram-positive bacteria. The concentrations of Q-35 which accumulated in S. aureus and E. coli were almost equal to ciprofloxacin, but in P. aeruginosa, Q-35 was lower than ciprofloxacin.
authors.affiliation: Department of Microbiology, Kyoto Pharmaceutical University, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ito
authors.forename: K
authors.initials: K
authors.lastname: Kojima
authors.forename: K
authors.initials: K
authors.lastname: Koizumi
authors.forename: H
authors.initials: H
authors.lastname: Nagano
authors.forename: T
authors.initials: T
authors.lastname: Nishino
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D024841:Fluoroquinolones; D015363:Quinolones / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
chemical_list: D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D015363:Quinolones; D059005:Topoisomerase II Inhibitors; C077155:balofloxacin