AM1 heats of formation for the reaction of alcohols with a series of β-lactams and aza-β-lactams: Design of novel β-lactamase inactivators

Abstract

AM1 heats of formation (H f) for the reaction of MeOH and EtOH with a series of β-lactams and aza-β-lactams are calculated. The ΔH f values for hemi-acetal and acyl/carbamoyl-enzyme intermediate formation are compared in the two series. These model calculations predict that the reaction of the β-lactamase active site serine hydroxyl with aza-β-lactams will afford carbamate intermediates which should be refractory to hydrolysis, thereby inhibiting the enzyme. Therefore, novel aza-β-lactams are putative β-lactamase inactivators based on semi-empirical computations.