N-Thiolated Bicyclic and Monocyclic β-Lactams

Abstract

In this study, we describe the synthesis and features of β-lactam ring systems having an alkylthio substituent on the lactam nitrogen center. The sulfur group acts to enhance the electrophilic character of the lactam carbonyl through electron withdrawal, and in bicyclic systems, reduces pyramidalization of the nitrogen center. Despite their electrophilic nature, these ring systems are chemically stable towards hydrolysis in aqueous media, but can be cleaved at the N–S bond by reducing agents such as triphenylphosphine. N-Methylthio substituted lactams favor a conformation having the sulfur–carbon bond of the SMe group aligned orthogonally with respect to the ring, with a facile interconversion between the cis and trans rotamers. These N-methylthio substituted lactams show potent antimicrobial behavior towards Staphylococcus aureus, including drug-resistant forms, and are not hydrolyzed by β-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 β-lactam drugs.