Synthesis and Antibacterial Activity of Novel Pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic Acid Derivatives Carrying the 3-Cyclopropylaminomethyl-4-substituted-1-pyrrolidinyl Group as a C-10 S

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• 作者：Yoshikazu Asahina ; Masaya Takei ; Tetsuya Kimura ; Yasumichi Fukuda
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：June 12, 2008
• 年：2008
• 卷：51
• 期：11
• 页码：3238 - 3249
• 全文大小：214K
• 年卷期：v.51,no.11(June 12, 2008)
• ISSN：1520-4804

文摘

Novel pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid derivatives 5−9 carrying a 3-cyclopropylaminomethyl-4-substituted-1-pyrrolidinyl moiety at the C-10 position were synthesized and their in vitro antibacterial activity, intravenous single-dose toxicity, convulsion inductive ability, and phototoxicity were evaluated. It appeared evident that compounds 5a, 6a, 8a, and 9a, which have a cis-oriented 4-methyl or 4-fluoro-3-cyclopropylaminomethyl-1-pyrrolidinyl moiety at the C-10 position, exhibited 2- to 16-fold more potent in vitro antibacterial activity than clinafloxacin against quinolone-resistant Gram-positive clinical isolates. Furthermore, it was obvious that introduction of a fluorine atom to the C-4 position of the 3-cyclopropylaminomethyl-1-pyrrolidinyl moiety reduced intraveneous single-dose acute toxicity and the convulsion inductive ability, and introduction of a fluorine atom to the C-3 methyl group of the pyridobenzoxazine nucleus eliminated the phototoxicity.