7-(2-Aminomethyl-1-azetidinyl)-4-oxoquinoline-3-carboxylic acids as potent antibacterial agents: design, synthesis, and antibacterial activity.
2-Aminomethyl-1-azetidinyl, -1-pyrrolidinyl, and -1-piperidinyl groups were designed as novel C-7 substituents for potential antibacterial quinolone agents. Of the three substituents, the 2-aminomethyl-1-azetidinyl group (compound 12a) was found to be the most favorable for enhancing the activity of the 6,8-difluoroquinoline molecule 12. Therefore the 2-aminomethyl-1-azetidinyl group was introduced into a variety of quinolines (giving 24-26a, and 28a) and naphthyridines (giving 31a and 32a). Through optical resolution of 1-benzylazetidine-2-carboxamide (19) and chiral synthesis of its R-isomer, both enantiomers of 2-aminomethyl-1-azetidinyl quinolines 12a and 24-26a were also prepared. The most active of all the compounds was 5-amino-6,8-difluoroquinoline (R)-26a. The activity of (R)-26a was more potent than those of the corresponding 1-piperazinyl derivative (3) and sparfloxacin (1), and was comparable to those of the corresponding 3-amino-1-pyrrolidinyl (4), 3-aminomethyl-1-pyrrolidinyl (5), and 3-amino-1-azetidinyl (6) derivatives.
Fujita
M
M
Discovery Research Laboratories II, Dainippon Pharmaceutical Company, Ltd., Osaka, Japan.
Chiba
K
K
Tominaga
Y
Y
Hino
K
K
D042462:4-Quinolones; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001384:Azetidines / Q000138:chemical synthesis* / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects*; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D042462:4-Quinolones; D000890:Anti-Infective Agents; D001384:Azetidines; D002264:Carboxylic Acids; D011804:Quinolines