Abstract
It has been reported that 2-(4-substituted thiazol-2-ylthio)-1β-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)-1β-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.
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Ueda, Y., Itoh, M., Sasaki, A. et al. SM-216601, a Novel Parenteral 1β-Methylcarbapenem: Structure-activity Relationships of Antibacterial Activity and Neurotoxicity in Mice. J Antibiot 58, 118–140 (2005). https://doi.org/10.1038/ja.2005.15
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DOI: https://doi.org/10.1038/ja.2005.15