N-thiolated bicyclic and monocyclic beta-lactams

In this study, we describe the synthesis and features of beta-lactam ring s ystems having an alkylthio substituent on the lactam nitrogen center. The s ulfur group acts to enhance the electrophilic character of the lactam carbo nyl through electron withdrawal and in bicyclic systems, reduces pyramidali zation of the nitrogen center. Despite their electrophilic nature, these ri ng systems are chemically stable towards hydrolysis in aqueous media, but c an be cleaved at the N-S bond by reducing agents such as triphenylphosphine . N-Methylthio substituted lactams favor a conformation having the sulfur-c arbon bond of the SMe group aligned orthogonally with respect to the ring, with a facile intel conversion between the cis and trans rotamers. These N- methylthio substituted lactams show potent antimicrobial behavior towards S taphylococcus aureus, including drug-resistant forms, and are not hydrolyze d by beta-lactamases. From the data presented, there is a strong suggestion that these lactams may operate through a chemical and biological mechanism of action that is different from all previous classes of beta-lactam drugs . (C) 2000 Elsevier Science Ltd. All rights reserved.