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Open AccessArticle

4-Amino-1,2,4-triazole-3-thione as a Promising Scaffold for the Inhibition of Serine and Metallo-β-Lactamases

1
Department of Life Sciences, University of Modena and Reggio Emilia, Via G. Campi 103, 41125 Modena, Italy
2
Department of Drug Science and Technology, University of Turin, Via P. Giuria 9, 10125 Turin, Italy
3
Department of Biology, University of Padua, Viale G. Colombo 3, 35121 Padua, Italy
4
Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, via Vetoio 1, 67100 L’Aquila, Italy
5
National Center of Biotechnology-CSIC, Calle Darwin 3, 28049 Madrid, Spain
*
Authors to whom correspondence should be addressed.
Pharmaceuticals 2020, 13(3), 52; https://doi.org/10.3390/ph13030052
Received: 11 February 2020 / Revised: 5 March 2020 / Accepted: 21 March 2020 / Published: 24 March 2020
(This article belongs to the Section Medicinal Chemistry)
The emergence of bacteria that co-express serine- and metallo- carbapenemases is a threat to the efficacy of the available β-lactam antibiotic armamentarium. The 4-amino-1,2,4-triazole-3-thione scaffold has been selected as the starting chemical moiety in the design of a small library of β-Lactamase inhibitors (BLIs) with extended activity profiles. The synthesised compounds have been validated in vitro against class A serine β−Lactamase (SBLs) KPC-2 and class B1 metallo β−Lactamases (MBLs) VIM-1 and IMP-1. Of the synthesised derivatives, four compounds showed cross-class micromolar inhibition potency and therefore underwent in silico analyses to elucidate their binding mode within the catalytic pockets of serine- and metallo-BLs. Moreover, several members of the synthesised library have been evaluated, in combination with meropenem (MEM), against clinical strains that overexpress BLs for their ability to synergise carbapenems. View Full-Text
Keywords: 4-amino-1,2,4-triazole-3-thione; bacterial resistance; structure-based drug design; non-covalent inhibition; thione/thiol tautomerism; broad-spectrum activity 4-amino-1,2,4-triazole-3-thione; bacterial resistance; structure-based drug design; non-covalent inhibition; thione/thiol tautomerism; broad-spectrum activity
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MDPI and ACS Style

Linciano, P.; Gianquinto, E.; Montanari, M.; Maso, L.; Bellio, P.; Cebrián-Sastre, E.; Celenza, G.; Blázquez, J.; Cendron, L.; Spyrakis, F.; Tondi, D. 4-Amino-1,2,4-triazole-3-thione as a Promising Scaffold for the Inhibition of Serine and Metallo-β-Lactamases. Pharmaceuticals 2020, 13, 52.

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