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

• मुख्य लेखकों: Pasquale Linciano (लेखक), Eleonora Gianquinto (लेखक), Martina Montanari (लेखक), Lorenzo Maso (लेखक), Pierangelo Bellio (लेखक), Esmeralda Cebrián-Sastre (लेखक), Giuseppe Celenza (लेखक), Jesús Blázquez (लेखक), Laura Cendron (लेखक), Francesca Spyrakis (लेखक), Donatella Tondi (लेखक)
• स्वरूप: पुस्तक
• प्रकाशित: MDPI AG, 2020-03-01T00:00:00Z.
• विषय: article
• ऑनलाइन पहुंच: Connect to this object online.
• Notes: 1424-8247; 10.3390/ph13030052
• Keywords: 4-amino-1,2,4-triazole-3-thione; bacterial resistance; structure-based drug design; non-covalent inhibition; thione/thiol tautomerism; broad-spectrum activity; Medicine; R; Pharmacy and materia medica; RS1-441
• Source: Pharmaceuticals, Vol 13, Iss 3, p 52 (2020)

The emergence of bacteria that co-express serine- and metallo- carbapenemases is a threat to the efficacy of the available <i>β</i>-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 <i>β</i>-Lactamase inhibitors (BLIs) with extended activity profiles. The synthesised compounds have been validated in vitro against class A serine <i>β−</i>Lactamase (SBLs) KPC-2 and class B1 metallo <i>β−</i>Lactamases (MBLs) VIM-1 and IMP-1. Of the synthesised derivatives, four compounds showed cross-class micromolar inhibition potency and therefore underwent <i>in silico</i> 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.