Article (Scientific journals)
4-Amino-1,2,4-triazole-3-thione-derived Schiff bases as metallo-beta-lactamase inhibitors
Gavara, L.; Sevaille, L.; De Luca, F. et al.
2020In European Journal of Medicinal Chemistry, 208, p. 112720
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Abstract :
[en] Resistance to β-lactam antibiotics in Gram-negatives producing metallo-β-lactamases (MBLs) represents a major medical threat and there is an extremely urgent need to develop clinically useful inhibitors. We previously reported the original binding mode of 5-substituted-4-amino/H-1,2,4-triazole-3-thione compounds in the catalytic site of an MBL. Moreover, we showed that, although moderately potent, they represented a promising basis for the development of broad-spectrum MBL inhibitors. Here, we synthesized and characterized a large number of 4-amino-1,2,4-triazole-3-thione-derived Schiff bases. Compared to the previous series, the presence of an aryl moiety at position 4 afforded an average 10-fold increase in potency. Among 90 synthetic compounds, more than half inhibited at least one of the six tested MBLs (L1, VIM-4, VIM-2, NDM-1, IMP-1, CphA) with Ki values in the microM to sub-microM range. Several were broad-spectrum inhibitors, also inhibiting the most clinically relevant VIM-2 and NDM-1. Active compounds generally contained halogenated, bicyclic aryl or phenolic moieties at position 5, and one substituent among o-benzoic, 2,4-dihydroxyphenyl, p-benzyloxyphenyl or 3-(m-benzoyl)-phenyl at position 4. The crystallographic structure of VIM-2 in complex with an inhibitor showed the expected binding between the triazole-thione moiety and the dinuclear centre and also revealed a network of interactions involving Phe61, Tyr67, Trp87 and the conserved Asn233. Microbiological analysis suggested that the compound antibacterial activity was limited by poor outer membrane penetration. This was supported by the ability of one compound to restore the susceptibility of an NDM-1-producing E. coli clinical strain toward several beta-lactams in the presence only of a sub-inhibitory concentration of colistin, a permeabilizing agent. Finally, some compounds were tested against the structurally similar di-zinc human glyoxalase II and found weaker inhibitors of the latter enzyme, thus showing a promising selectivity towards MBLs.
Disciplines :
Biochemistry, biophysics & molecular biology
Microbiology
Author, co-author :
Gavara, L.
Sevaille, L.
De Luca, F.
Mercuri, Paola ;  Université de Liège - ULiège > Département des sciences de la vie > Macromolécules biologiques
Bebrone, Carine ;  Université de Liège - ULiège > GIGA Platforms
Feller, Georges ;  Université de Liège - ULiège > Département des sciences de la vie > Laboratoire de biochimie
Legru, A.
Cerboni, G.
Tanfoni, S.
Baud, D.
Cutolo, G.
Bestgen, B.
Chelini, G.
Verdirosa, F.
Sannio, F.
Pozzi, C.
Benvenuti, M.
Kwapien, K.
Fischer, M.
Becker, K.
Frère, Jean-Marie ;  Université de Liège - ULiège > Département des sciences de la vie > Macromolécules biologiques
Mangani, S.
Gresh, N.
Berthomieu, D.
Galleni, Moreno ;  Université de Liège - ULiège > Département des sciences de la vie > Macromolécules biologiques
Docquier, Jean-Denis ;  Université de Liège - ULiège > InBioS
Hernandez, J.-F.
More authors (17 more) Less
Language :
English
Title :
4-Amino-1,2,4-triazole-3-thione-derived Schiff bases as metallo-beta-lactamase inhibitors
Publication date :
2020
Journal title :
European Journal of Medicinal Chemistry
ISSN :
0223-5234
eISSN :
1768-3254
Publisher :
Elsevier, Netherlands
Volume :
208
Pages :
112720
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
ANR - Agence Nationale de la Recherche [FR]
Funding number :
Agence Nationale de la Recherche, France (ANR-14-CE16-0028-01)
Available on ORBi :
since 04 August 2020

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