Synthesis and antibacterial activity of novel pyridobenzoxazine analogues.
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.
Kawakami
K
K
New Product Research Laboratories I, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
Atarashi
S
S
Kimura
Y
Y
Takemura
M
M
Hayakawa
I
I
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
D000900:Anti-Bacterial Agents; D010078:Oxazines