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

A series of monocyclic azetidinones were prepared, bearing, at position C-3 , an acetylamino or a bromo substituent, at position N-1, a carboxymethyl g roup protected as p-nitrobenzyl ester (PNB) and alpha-functionalized with a potential leaving group (LG). These structures were designed as potential suicide-inhibitors of enzymes containing a serine nucleophile in their acti ve site. The beta-lactam ring of these molecules was found to be stable in phosphate buffer (pH 7.5), but the PNB ester was rapidly cleaved. This cons titutes 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 = SO2Ph) was observed under hydrolytic conditi ons. The 1,3-disubstituted azetidinones were inactive against beta-lactamas es of classes A, B, C, and D. Three compounds behaved as weak reversible in hibitors of porcine pancreatic elastase (PPE). (C) 1999 Elsevier Science Lt d. All rights reserved.