Carbamylmethyl Mercaptoacetate Thioether: A NovelScaffold for the Development of L1 Metallo-β-lactamase Inhibitors

摘要

Given the clinical importance of metallo-β-lactamases (MβLs), a new scaffold, N-substituted carbamylmethyl mercaptoacetate thioether, was constructed. The obtained molecules >1–>16 inhibited MβLs from all three subclasses, but preferentially L1 from subclass B3. Compound >9 with a p-carboxyphenyl substituent exhibited the broadest spectrum with at least 70% inhibition of enzymes from all subclasses at 100 μM, while compound >5 with a p-methylphenyl substituent was the most potent inhibitor of any individual enzyme, with 97% inhibition at 100 μM and an IC50 value of 0.41 μM against L1. Isothermal titration calorimetry assays corroborate findings from UV–vis spectrophotometric assays that the inhibition of L1 by >5 is dose-dependent. Docking studies suggest that the carboxyl group, the sulfide atom, and the carbonyl group of the carbamyl coordinate Zn2 in a chelating fashion. Using E. coli cells expressing L1, >6 and >8 were able to decrease cefazolin minimum inhibitory concentration 8-fold.