Inhibitory Activity on DNA Gyrase and Intracellular Accumulation of Quinolones : Structure-Activity Relationship of Q-35 Analogs

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Q-35,1-cyclopropy-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methylaminopiperidine-1-yl)-4-oxoquinoline-3-car-boxylic 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 purifled 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 (IC_<50>) 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 68μg/ml, respectively. The IC_<50> on gyrase from P. aeruginosa were 11,5.2,and 17 μg/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.
社団法人日本薬学会の論文
1994-07-15