1,2,4-Triazole-3-thione compounds as inhibitors of dizinc metallo-β-lactamases

Sevaille, Laurent, Gavara, Laurent, Bebrone, Carine, De Luca, Filomena, Nauton, Lionel, Achard, Maud, Mercuri, Paola, Tanfoni, Silvia, Borgianni, Luisa, Guyon, Carole, Lonjon, Pauline, Turan-Zitouni, Gülhan, Dzieciolowski, Julia, Becker, Katja, Bénard, Lionel, Condon, Ciaran, Maillard, Ludovic, Martinez, Jean, Frère, Jean-Marie, Dideberg, Otto, Galleni, Moreno, Docquier, Jean-Denis and Hernandez, Jean-François (2017) 1,2,4-Triazole-3-thione compounds as inhibitors of dizinc metallo-β-lactamases. ChemMedChem, 12 12: 972-985. doi:10.1002/cmdc.201700186

Author Sevaille, Laurent
Gavara, Laurent
Bebrone, Carine
De Luca, Filomena
Nauton, Lionel
Achard, Maud
Mercuri, Paola
Tanfoni, Silvia
Borgianni, Luisa
Guyon, Carole
Lonjon, Pauline
Turan-Zitouni, Gülhan
Dzieciolowski, Julia
Becker, Katja
Bénard, Lionel
Condon, Ciaran
Maillard, Ludovic
Martinez, Jean
Frère, Jean-Marie
Dideberg, Otto
Galleni, Moreno
Docquier, Jean-Denis
Hernandez, Jean-François
Title 1,2,4-Triazole-3-thione compounds as inhibitors of dizinc metallo-β-lactamases
Journal name ChemMedChem   Check publisher's open access policy
ISSN 1860-7187
Publication date 2017-06-21
Sub-type Article (original research)
DOI 10.1002/cmdc.201700186
Open Access Status Not yet assessed
Volume 12
Issue 12
Start page 972
End page 985
Total pages 14
Place of publication Weinheim, Germany
Publisher Wiley - V C H Verlag GmbH & Co. KGaA
Language eng
Subject 1313 Molecular Medicine
3000 Pharmacology, Toxicology and Pharmaceutics
1605 Organic Chemistry
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 IC 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 IC values toward plasmodial glyoxalase II were in the 10 μm range.
Keyword Antibiotics
Bacterial resistance
Nitrogen heterocycles
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID ANR-06-BLAN-0086
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
School of Chemistry and Molecular Biosciences
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 4 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 4 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Fri, 23 Jun 2017, 01:27:52 EST