Azolylthioacetamide: A Highly Promising Scaffold for the Development of Metallo-β-lactamase Inhibitors

• DOI: 10.1021/ml500534c
• Publication Date: 2015-02-13T00:07:41Z
• Authors: Shao-Kang Yang; Joon S. Kang; Peter Oelschlaeger; Ke-Wu Yang
• Keywords: Carboxylate; Docking (animal)

A new scaffold, azolylthioacetamide, was constructed and assayed against metallo-β-lactamases (MβLs). The obtained molecules specifically inhibited MβL ImiS, 1c found to be the most potent inhibitor, with a Ki = 1.2 μM using imipenem as substrate. Structure–activity relationships reveal that aromatic carboxyl improves inhibitory activity of inhibitors, but aliphatic does not. Compounds 1c–d 1h–i showed best antibacterial activities E. coli BL21(DE3) cells producing CcrA or resulting in 32- 8-fold reduction MIC values, respectively; 1f–j resulted P. aeruginosa. Docking studies revealed 1a, 1c, 1d fit tightly into substrate binding site CphA proxy for ImiS carboxylate forming interactions Lys224, Zn(II) ion, backbone Asn233, hydrophobic portions inhibitors aligning patches protein surface.