Discovery of [1,2,4]Triazole Derivatives As New Metallo-β-Lactamase Inhibitors

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2019 Dec 28

PMID 31877988

Citations 3

Authors

Chen Yuan

Jie Yan

Chen Song

Fan Yang

Chao Li

Cheng Wang

Huiling Su

Wei Chen

Lijiao Wang

Zhouyu Wang

Shan Qian

Lingling Yang

Affiliations

Soon will be listed here.

Abstract

The emergence and spread of metallo-β-lactamase (MBL)-mediated resistance to β-lactam antibacterials has already threatened the global public health. A clinically useful MBL inhibitor that can reverse β-lactam resistance has not been established yet. We here report a series of [1,2,4]triazole derivatives and analogs, which displayed inhibition to the clinically relevant subclass B1 (Verona integron-encoded MBL-2) VIM-2. 3-(4-Bromophenyl)-6,7-dihydro-5-[1,2,4]triazolo [3,4-][1,3]thiazine () manifested the most potent inhibition with an IC (half-maximal inhibitory concentration) value of 38.36 μM. Investigations of against other B1 MBLs and the serine β-lactamases (SBLs) revealed the selectivity to VIM-2. Molecular docking analyses suggested that bound to the VIM-2 active site via the triazole involving zinc coordination and made hydrophobic interactions with the residues Phe61 and Tyr67 on the flexible L1 loop. This work provided new triazole-based MBL inhibitors and may aid efforts to develop new types of inhibitors combating MBL-mediated resistance.

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