Synthesis, reactivity and biochemical evaluation of 1,3-substituted azetidin-2-ones as enzyme inhibitors

Abstract

A series of monocyclic azetidinones were prepared, bearing, at position C-3, an acetylamino or a bromo substituent, at position N-1, a carboxymethyl group protected as p-nitrobenzyl ester (PNB) and α-functionalized with a potential leaving group (LG). These structures were designed as potential suicide-inhibitors of enzymes containing a serine nucleophile in their active site. The β-lactam ring of these molecules was found to be stable in phosphate buffer (pH 7.5), but the PNB ester was rapidly cleaved. This constitutes a practical method of in situ deprotection. Depending on the nature of the LG group on the carboxymethyl chain, substitution of this group (LG = F) or decarboxylation (LG = SO 2Ph) was observed under hydrolytic conditions. The 1,3-disubstituted azetidinones were inactive against β-lactamases of classes A, B, C, and D. Three compounds behaved as weak reversible inhibitors of porcine pancreatic elastase (PPE).