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Open AccessArticle

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

1
College of Food and Bioengineering, Xihua University, Chengdu 610039, China
2
College of Science, Xihua University, Chengdu 610039, China
*
Authors to whom correspondence should be addressed.
Molecules 2020, 25(1), 56; https://doi.org/10.3390/molecules25010056
Received: 18 November 2019 / Revised: 16 December 2019 / Accepted: 17 December 2019 / Published: 23 December 2019
(This article belongs to the Section Medicinal Chemistry)
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 IC50 (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. View Full-Text
Keywords: β-lactam resistance; metallo-β-lactamase; serine β-lactamase; VIM-2; triazole β-lactam resistance; metallo-β-lactamase; serine β-lactamase; VIM-2; triazole
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MDPI and ACS Style

Yuan, C.; Yan, J.; Song, C.; Yang, F.; Li, C.; Wang, C.; Su, H.; Chen, W.; Wang, L.; Wang, Z.; Qian, S.; Yang, L. Discovery of [1,2,4]Triazole Derivatives as New Metallo-β-Lactamase Inhibitors. Molecules 2020, 25, 56. https://doi.org/10.3390/molecules25010056

AMA Style

Yuan C, Yan J, Song C, Yang F, Li C, Wang C, Su H, Chen W, Wang L, Wang Z, Qian S, Yang L. Discovery of [1,2,4]Triazole Derivatives as New Metallo-β-Lactamase Inhibitors. Molecules. 2020; 25(1):56. https://doi.org/10.3390/molecules25010056

Chicago/Turabian Style

Yuan, Chen; Yan, Jie; Song, Chen; Yang, Fan; Li, Chao; Wang, Cheng; Su, Huiling; Chen, Wei; Wang, Lijiao; Wang, Zhouyu; Qian, Shan; Yang, Lingling. 2020. "Discovery of [1,2,4]Triazole Derivatives as New Metallo-β-Lactamase Inhibitors" Molecules 25, no. 1: 56. https://doi.org/10.3390/molecules25010056

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