title: 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 substituent.
abstract: 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.
authors.affiliation: Discovery Research Laboratories, Kyorin Pharmaceutical Co Ltd, Nogi, Nogi-Machi, Shimotsuga-Gun, Tochigi, Japan. yoshikazu.asahina@mb.kyorin-pharm.co.jp
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Asahina
authors.forename: Masaya
authors.initials: M
authors.lastname: Takei
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kimura
authors.forename: Yasumichi
authors.initials: Y
authors.lastname: Fukuda
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D048588:Benzoxazines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D024881:Drug Resistance, Bacterial; D024841:Fluoroquinolones / Q000494:pharmacology; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000302:isolation & purification; D006094:Gram-Positive Bacteria / Q000187:drug effects / Q000302:isolation & purification; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D015363:Quinolones / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C530306:10-(3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl)-9-fluoro-3-fluoromethyl-2,3-dihydro-7-oxo-7H-pyrido(1,2,3-de)(1,4)benzoxazine-6-carboxylic acid; D000900:Anti-Bacterial Agents; D048588:Benzoxazines; D024841:Fluoroquinolones; D011759:Pyrrolidines; D015363:Quinolones; C057477:clinafloxacin