Research Division, Sumitomo Pharmaceuticals Co., Ltd., 1-98, Kasugade Naka 3-Chome, Konohana-ku, Osaka 554-0022, Japan

Correspondence: M. Sunagawa, Research Division, Sumitomo Pharmaceuticals Co., Ltd., 1-98, Kasugade Naka 3-Chome, Konohana-ku, Osaka 554-0022, Japan. E-mail: sunagawa@sumitomopharm.co.jp.

Received 26 November 2004; Accepted 1 February 2005.

Abstract

It has been reported that 2-(4-substituted thiazol-2-ylthio)-1-methyl-carbapenems exhibit potent activity against methicillin-resistant staphylococci (MRS) and vancomycin-resistant enterococci (VRE). In order to develop a novel broad-spectrum carbapenem, the structure-activity relationships of a series of 2-(4-tetrahydropyridinylthiazol-2-ylthio)-1-methylcarbapenems and 4-dihydropyrrolyl thiazole analogs were investigated with regard to their activity against Gram-positive and especially Gram-negative bacteria and also their convulsant activity, which is a major side effect concern of carbapenems. The introduction of substituent(s) on the dihydropyrrole moiety did not cause remarkable changes in anti-MRS and VRE activities, but tended to lower the anti-Gram-negative bacterial activity except in some cases of methyl group introduction. These substitutions did however cause a reduction of the convulsant activity, which was affected by the size and also the configuration of the substituent. In the case of SM-216601 (6), introduction of a methyl group brought about significant reduction in neurotoxicity while maintaining favorable anti-Gram-negative bacterial activity.