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

摘要

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