新型四环吡啶酮羧酸系列的合成与抗菌活性

Synthesis and antibacterial activity of a new series of tetracyclic pyridone carboxylic acids.

作者信息

Jinbo Y, Kondo H, Inoue Y, Taguchi M, Tsujishita H, Kotera Y, Sakamoto F, Tsukamoto G

机构信息

New Drug Research Laboratories, Kanebo, Ltd., Osaka, Japan.

出版信息

J Med Chem. 1993 Sep 3;36(18):2621-6. doi: 10.1021/jm00070a005.

DOI:10.1021/jm00070a005

PMID:8410974

Abstract

A series of novel tetracyclic pyridone carboxylic acids replacing the 10-position oxygen atom of 9,1-(epoxymethano)-7-fluoro-8-(4-methyl-1-piperazinyl)-5-oxo-5H-thiazolo [3,2-alpha]quinoline-4-carboxylic acid by imino groups (NR; R = Me, Et, c-Pr, allyl, Ph, benzyl), a sulfur atom, or a carbonyl group was prepared and evaluated for antibacterial activity and inhibitory activity on DNA gyrase isolated from E. coli KL-16. The in vitro antibacterial potency and DNA gyrase inhibitory activity were found to be in the following order: NMe > or = O > S >> C = O. Moreover, a methyl group was the optimal alkyl substituent at the 10-position nitrogen atom for antibacterial activity and for DNA gyrase inhibitory activity. 7-Fluoro-9,1-[(N-methylimino)methano]-8- (4-methyl-1-piperazinyl)-5-oxo-5H-thiazolo[3,2-alpha]quinoline-4-carboxy lic acid (10-NCH3) showed potent in vivo antibacterial activity.

摘要

通过亚氨基（NR；R = 甲基、乙基、环丙基、烯丙基、苯基、苄基）、硫原子或羰基取代9,1-(环氧亚甲基)-7-氟-8-(4-甲基-1-哌嗪基)-5-氧代-5H-噻唑并[3,2-α]喹啉-4-羧酸的10位氧原子，制备了一系列新型四环吡啶酮羧酸，并对其抗菌活性以及对从大肠杆菌KL-16分离的DNA回旋酶的抑制活性进行了评估。发现体外抗菌效力和DNA回旋酶抑制活性按以下顺序排列：NMe ≥ O > S >> C = O。此外，对于抗菌活性和DNA回旋酶抑制活性而言，甲基是10位氮原子上的最佳烷基取代基。7-氟-9,1-[(N-甲基亚氨基)亚甲基]-8-(4-甲基-1-哌嗪基)-5-氧代-5H-噻唑并[3,2-α]喹啉-4-羧酸（10-NCH3）显示出强效的体内抗菌活性。