title: Synthesis and antibacterial activity of novel pyridobenzoxazine analogues.
abstract: A series of novel LVFX (7) analogues bearing 4,4-dialkyl-3-aminopyrrolidines at the C-10 position of pyridobenzoxazine was synthesized and their antibacterial activities, pharmacokinetics and acute toxicities in animals were evaluated. Non-alkylated pyrrolidine derivative 26a showed greater activity than LVFX (7) against gram-positive and gram-negative bacteria including Pseudomonas aeruginosa, but 26a possessed high acute toxicity in mice and unfavorable pharmacokinetics in rats. When compared with 26a, 4,4-dialkylated derivatives 26c, e.g. showed more potent activity against gram-positive bacteria along with an improvement of pharmacokinetics and reduction of acute toxicity. Increases in lipophilicity by alkylation on the pyrrolidine ring resulted in a good influence on the above profiles.
authors.affiliation: New Product Research Laboratories I, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kawakami
authors.forename: S
authors.initials: S
authors.lastname: Atarashi
authors.forename: Y
authors.initials: Y
authors.lastname: Kimura
authors.forename: M
authors.initials: M
authors.lastname: Takemura
authors.forename: I
authors.initials: I
authors.lastname: Hayakawa
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D001419:Bacteria / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D051379:Mice; D008826:Microbial Sensitivity Tests; D010078:Oxazines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D010078:Oxazines