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

ACS Medicinal Chemistry Letters
Ya-Nan ChangKe-Wu Yang

Abstract

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.

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Citations

Oct 6, 2018·MedChemComm·Kamaleddin H M E Tehrani, Nathaniel I Martin
Mar 30, 2019·Chemical Biology & Drug Design·Cheng ShiHeng Zheng
Apr 4, 2018·Current Medicinal Chemistry·Raivis Zalubovskis, Jean-Yves Winum
Feb 6, 2020·Chemical Communications : Chem Comm·Cheng ChenLe-Yun Sun
Aug 19, 2017·ACS Infectious Diseases·Kamaleddin Haj Mohammad Ebrahim Tehrani, Nathaniel I Martin
Aug 15, 2018·Journal of Chemical Information and Modeling·Joon S KangPeter Oelschlaeger

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