Design, synthesis and biological evaluations of novel 7-[3-(1-aminocycloalkyl)pyrrolidin-1-yl]-6-desfluoro-8-methoxyquinolones with potent antibacterial activity against multi-drug resistant Gram-posi

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• 作者：Rie Miyauchi ; Katsuhiro Kawakami ; Masao Ito ; Norikazu Matsuhashi ; Hitoshi Ohki ; Hiroaki Inagaki ; Hisashi Takahashi ; Makoto Takemura
• 关键词：6-Desfluoro-quinolones ; Type II topoisomerases ; Gram-positive bacteria ; Antibacterial agents
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2009
• 出版时间：1 October 2009
• 年：2009
• 卷：17
• 期：19
• 页码：6879-6889
• 全文大小：705 K

文摘

A series of novel 6-desfluoro [des-F(6)] and 6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methoxyquinolones bearing 3-(1-aminocycloalkyl)pyrrolidin-1-yl substituents at the C-7 position (1–6) was synthesized to obtain potent drugs for nosocomial infections caused by Gram-positive pathogens. The des-F(6) compounds 4–6 exhibited at least four times more potent activity against representative Gram-positive bacteria than ciprofloxacin or moxifloxacin. Among the derivatives, 7-[(3R)-3-(1-aminocyclopropan-1-yl)pyrrolidin-1-yl] derivative 4, which showed favorable profiles in preliminary toxicological and non-clinical pharmacokinetic studies, exhibited potent antibacterial activity against clinically isolated Gram-positive pathogens that had become resistant to one or more antibiotics.