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ChemMedChem. 2017 Jun 21;12(12):972-985. doi: 10.1002/cmdc.201700186. Epub 2017 Jun 12.

1,2,4-Triazole-3-thione Compounds as Inhibitors of Dizinc Metallo-β-lactamases.

Author information

1
Institut des Biomolécules Max Mousseron, UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier cedex 5, France.
2
Laboratoire de Macromolécules Biologiques, Centre d'Ingénierie des Protéines, Université de Liège, Allée du 6 août B6, Sart-Tilman, 4000, Liège, Belgium.
3
Present address: Symbiose Biomaterials S.A., GIGA Bât. B34, 1 avenue de l'Hôpital, 4000, Liège, Belgium.
4
Dipartimento di Biotecnologie Mediche, Università di Siena, 53100, Siena, Italy.
5
Institut de Biologie Structurale-Jean-Pierre Ebel, UMR5075 CNRS, CEA, Université Joseph Fourier, 41 rue Jules Horowitz, 38027, Grenoble cedex 1, France.
6
Present address: Institut de Chimie de Clermont-Ferrand, UMR6296 CNRS, Université Clermont Auvergne, 63000, Clermont-Ferrand, France.
7
EMBL Outstation c/o DESY, Notkestrasse 85, 22603, Hamburg, Germany.
8
Present address: School of Chemistry and Molecular Bioscience, University of Queensland, St. Lucia, Brisbane, QLD, 4072, Australia.
9
Present address: CERN, HSE/SEE/SI, 1211, Geneva 23, Switzerland.
10
Department of Pharmaceutical Chemistry, Anadolu University, Faculty of Pharmacy, 26470, Eskisehir, Turkey.
11
Chair of Biochemistry and Molecular Biology, Interdisciplinary Research Center, Justus Liebig University, Heinrich-Buff-Ring 26-32, 35392, Giessen, Germany.
12
UMR8226, CNRS, Université Pierre et Marie Curie, Institut de Biologie Physico-Chimique, 13 rue Pierre et Marie Curie, 75005, Paris, France.
13
UMR8261, CNRS, Université Paris-Diderot, Institut de Biologie Physico-Chimique, 13 rue Pierre et Marie Curie, 75005, Paris, France.

Abstract

Metallo-β-lactamases (MBLs) cause resistance of Gram-negative bacteria to β-lactam antibiotics and are of serious concern, because they can inactivate the last-resort carbapenems and because MBL inhibitors of clinical value are still lacking. We previously identified the original binding mode of 4-amino-2,4-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione (compound IIIA) within the dizinc active site of the L1 MBL. Herein we present the crystallographic structure of a complex of L1 with the corresponding non-amino compound IIIB (1,2-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione). Unexpectedly, the binding mode of IIIB was similar but reverse to that of IIIA. The 3 D structures suggested that the triazole-thione scaffold was suitable to bind to the catalytic site of dizinc metalloenzymes. On the basis of these results, we synthesized 54 analogues of IIIA or IIIB. Nineteen showed IC50 values in the micromolar range toward at least one of five representative MBLs (i.e., L1, VIM-4, VIM-2, NDM-1, and IMP-1). Five of these exhibited a significant inhibition of at least four enzymes, including NDM-1, VIM-2, and IMP-1. Active compounds mainly featured either halogen or bulky bicyclic aryl substituents. Finally, some compounds were also tested on several microbial dinuclear zinc-dependent hydrolases belonging to the MBL-fold superfamily (i.e., endonucleases and glyoxalase II) to explore their activity toward structurally similar but functionally distinct enzymes. Whereas the bacterial tRNases were not inhibited, the best IC50 values toward plasmodial glyoxalase II were in the 10 μm range.

KEYWORDS:

antibiotics; bacterial resistance; lactams; metalloenzymes; nitrogen heterocycles

PMID:
28505394
DOI:
10.1002/cmdc.201700186
[Indexed for MEDLINE]

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