- 著者
- 岡田 哲夫 江角 清志 山川 眞透 佐藤 久夫 辻 照二 津島 忠彦 元川 清司 小松 良英
- 出版者
- The Pharmaceutical Society of Japan
- 雑誌
- Chemical and Pharmaceutical Bulletin (ISSN:00092363)
- 巻号頁・発行日
- vol.41, no.1, pp.126-131, 1993-01-15 (Released:2008-03-31)
- 参考文献数
- 25
- 被引用文献数
- 19 24
Quantitative structure-activity relationships (QSAR) of various 7-(3-substituted-azetidin-1-yl)-1-cyclopropyl-6, 8-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acids, 14-25, were studied to clarify the structural requirements for 3-substituted azetidines to potentiate antibacterial activity. A good parabolic relationship seemed to exist between the relative mean antibacterial activity indices against five representative gram-negative bacteria, GNM, and the calculated hydrophobic parameters, CLOG P, of these molecules. The CLOG P value of the most potent derivative was predicted to be around 2.3. On the other hand, against five representative gram-positive bacteria, the relative mean antibacterial activity indices, GPM, remained high and rather constant regardless of structural variation in the azetidine moiety. In order to confirm these findings, the QSAR analysis was extended with success to the quinolonecarboxylic acids, 26-34, which bear various substituted pyrrolidine, piperazine and piperidine derivatives instead of azetidines. The findings showed that the introduction of any amide substituent group to these heterocyclic amine moieties would lead to marked decrease in GNM, whereas incorporation of some amino substituent groups at a position two or three carbons remote from the N-1 position resulted in great enhancement of GNM. As azetidine quinolones exhibited somewhat low in vivo antibacterial activities, possibly reflecting their lesser bioavailability, we finally selected 3-amino-4-methoxypyrrolidine as one of the most promising C-7 substituent groups based on our QSAR analysis.
- 著者
- 岡田 哲夫 佐藤 久夫 辻 照二 津島 忠彦 中井 博 吉田 正 松浦 眞三
- 出版者
- The Pharmaceutical Society of Japan
- 雑誌
- Chemical and Pharmaceutical Bulletin (ISSN:00092363)
- 巻号頁・発行日
- vol.41, no.1, pp.132-138, 1993-01-15 (Released:2008-03-31)
- 参考文献数
- 12
- 被引用文献数
- 13 19
A new series of quinolone derivatives 3a-I bearing 3-amino-4-methoxypyrrolidines of different configurations and chirality were synthesized and their antibacterial activities as well as some of their toxicological properties were examined. As predicted by our previous quantitative structure-activity relationships (QSAR) analysis of C-7 heterocyclic amine substituted quinolonecarboxylic acid antibacterial agents, these pyrrolidine derivatives showed higher in vitro and in vivo antibacterial activities against both gram-positive and gram-negative bacteria than the analogs bearing various 3-substituted azetidines. Furthermore, the amino and methoxy substituent groups on the pyrrolidine ring exhibited strong configurational and chiral effects on the in vitro and in vivo antibacterial activities of these compounds : (1) cis compounds showed higher antibacterial activities against most of the pathogens examined : (2) N-methylation of the 3-amino group on the pyrrolidine ring lowered in vitro but not in vivo antibacterial activities, particularly leading to superior in vivo anti-pseudomonal activity; (3) the (3'S, 4'R)-derivative showed substantially higher activity that the (3'R, 4'S)-one. These findings led to the selection of compound 3k for further evaluation as it possessed the highest in vivo antibacterial activity and no cytotoxicity.