Triazolylthioacetamide: A Valid Scaffold for the Development of New Delhi Metallo-β-Lactmase-1 (NDM-1) Inhibitors

The metallo-beta-lactamases (M beta Ls) cleave the beta-lactam ring of beta-lactam antibiotics, conferring resistance against these drugs to bacteria. Twenty-four triazolylthioacetamides were prepared and evaluated as inhibitors of representatives of the three subclasses of M beta Ls. All these compounds exhibited specific inhibitory activity against NDM-1 with an IC50 value range of 0.15-1.90 mu M, but no activity against CcrA, ImiS, and L1 at inhibitor concentrations of up to 10 mu M. Compounds 4d and 6c are partially mixed inhibitors with K-i values of 0.49 and 0.63 mu M using cefazolin as the substrate. Structure activity relationship studies reveal that replacement of hydrogen on the aromatic ring by chlorine, heteroatoms, or alkyl groups can affect bioactivity, while leaving the aromatic ring of the triazolylthiols unmodified maintains the inhibitory potency. Docking studies reveal that the typical potent inhibitors of NDM-1, 4d and 6c, form stable interactions in the active site of NDM-1, with the triazole bridging Zn1 and Zn2, and the amide interacting with Lys 211 (Lys224).