1,2,4-Triazole-3-thione analogues with an arylakyl group at position 4 as metallo-β-lactamase inhibitors

Autor: Laurent, Gavara, Federica, Verdirosa, Laurent, Sevaille, Alice, Legru, Giuseppina, Corsica, Lionel, Nauton, Paola, Sandra Mercuri, Filomena, Sannio, Filomena, De Luca, Margot, Hadjadj, Giulia, Cerboni, Yen, Vo Hoang, Patricia, Licznar-Fajardo, Moreno, Galleni, Jean-Denis, Docquier, Jean-François, Hernandez
Přispěvatelé: Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Université de Montpellier (UM), Università degli Studi di Siena = University of Siena (UNISI), Hydrosciences Montpellier (HSM), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Université de Liège
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Bioorganic and Medicinal Chemistry
Bioorganic and Medicinal Chemistry, 2022, 72, pp.116964. ⟨10.1016/j.bmc.2022.116964⟩
ISSN: 0968-0896
1464-3391
DOI: 10.1016/j.bmc.2022.116964⟩
Popis: International audience; Metallo-β-lactamases (MBLs) represent an increasingly serious threat to public health because of their increased prevalence worldwide in relevant opportunistic Gram-negative pathogens. MBLs efficiently inactivate widely used and most valuable β-lactam antibiotics, such as oxyiminocephalosporins (ceftriaxone, ceftazidime) and the last-resort carbapenems. To date, no MBL inhibitor has been approved for therapeutic applications. We are developing inhibitors characterized by a 1,2,4-triazole-3-thione scaffold as an original zinc ligand and few promising series were already reported. Here, we present the synthesis and evaluation of a new series of compounds characterized by the presence of an arylalkyl substituent at position 4 of the triazole ring. The alkyl link was mainly an ethylene, but a few compounds without alkyl or with an alkyl group of various lengths up to a butyl chain were also synthesized. Some compounds in both sub-series were micromolar to submicromolar inhibitors of tested VIM-type MBLs. A few of them were broad-spectrum inhibitors, as they showed significant inhibitory activity on NDM-1 and, to a lesser extent, IMP-1. Among these, several inhibitors were able to significantly reduce the meropenem MIC on VIM-1- and VIM-4- producing clinical isolates by up to 16-fold. In addition, ACE inhibition was absent or moderate and one promising compound did not show toxicity toward HeLa cells at concentrations up to 250 μM. This series represents a promising basis for further exploration. Finally, molecular modelling of representative compounds in complex with VIM-2 was performed to study their binding mode.
Databáze: OpenAIRE
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