1, 2, 4-Triazole-3-thione analogues with an arylakyl group at position 4 as metallo-β-lactamase inhibitors. (15th October 2022)

• Record Type: Journal Article
• Authors: Gavara, Laurent; Verdirosa, Federica; Sevaille, Laurent; Legru, Alice; Corsica, Giuseppina; Nauton, Lionel; Sandra Mercuri, Paola; Sannio, Filomena; De Luca, Filomena; Hadjadj, Margot; Cerboni, Giulia; Vo Hoang, Yen; Licznar-Fajardo, Patricia; Galleni, Moreno; Docquier, Jean-Denis; Hernandez, Jean-François
• Is Part Of: Bioorganic & medicinal chemistry. Volume 72(2022)
• Publication Date: 2022-10-15
• Subjects: Metallo-β-Lactamase -- 1, 2, 4-triazole-3-thione -- Bacterial resistance -- β-lactam antibiotic; ACE angiotensin-converting enzyme -- CLSI Clinical and Laboratory Standards Institute -- DCM dichloromethane -- DFT density functional theory -- DMF dimethylformamide -- DMSO dimethylsulfoxide -- DPT di(2-pyridyl) thionocarbonate -- FIC fractional inhibitory concentration -- HEPES 4-(2-Hydroxyethyl)-1-piperazine-ethanesulfonic acid -- IMP imipenemase -- KPC Klebsiella pneumoniae Carbapenemase -- MBL metallo-β-lactamase -- MEM meropenem -- MIC minimum inhibitory concentration -- NDM New Delhi Metallo-β-lactamase -- OXA oxacillinase -- PDB protein data bank -- SBL serine-β-lactamase -- VIM Verona Integron-borne Metallo-β-lactamase; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2022.116964
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: Fourty-eight 1, 2, 4-triazole-3-thione compounds with an arylalkyl moiety at position 4 are reported. Several analogues were broad-spectrum inhibitors of clinically important MBLs. Several analogues restored meropenem activity on VIM-1/4-producing clinical isolates. The binding mode of three compounds to VIM-2 was studied by molecular modelling. Abstract: 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.