1. Discovery of [1,2,4]Triazole Derivatives as New Metallo-β-Lactamase Inhibitors.
- Author
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Yuan, Chen, Yan, Jie, Song, Chen, Yang, Fan, Li, Chao, Wang, Cheng, Su, Huiling, Chen, Wei, Wang, Lijiao, Wang, Zhouyu, Qian, Shan, and Yang, Lingling
- Subjects
TRIAZOLE derivatives ,HYDROPHOBIC interactions ,MANNOSE-binding lectins ,MOLECULAR docking ,LACTAMS ,WORLD health - 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-5H-[1,2,4]triazolo [3,4-b][1,3]thiazine (5l) manifested the most potent inhibition with an IC
50 (half-maximal inhibitory concentration) value of 38.36 μM. Investigations of 5l against other B1 MBLs and the serine β-lactamases (SBLs) revealed the selectivity to VIM-2. Molecular docking analyses suggested that 5l 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. [ABSTRACT FROM AUTHOR]- Published
- 2020
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