Triazolylthioacetamide: A Valid Scaffold for the Development of New Delhi Metallo-β-Lactmase-1 (NDM-1) Inhibitors.
The metallo-β-lactamases (MβLs) cleave the β-lactam ring of β-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 MβLs. All these compounds exhibited specific inhibitory activity against NDM-1 with an IC50 value range of 0.15-1.90 μM, but no activity against CcrA, ImiS, and L1 at inhibitor concentrations of up to 10 μM. Compounds 4d and 6c are partially mixed inhibitors with K i values of 0.49 and 0.63 μM 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).
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry and Materials Science, Northwest University, Xi'an 710127, P. R. China; College of Chemistry and Chemical Engineering, Baoji University of Arts and Sciences, Baoji 721016, P. R. China.
Le
L
Zhai
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry and Materials Science, Northwest University , Xi'an 710127, P. R. China.
Yi-Lin
YL
Zhang
Department of Biological Sciences, California State Polytechnic University , 3801 West Temple Avenue, Pomona, California 91768, United States.
Joon S
JS
Kang
Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences , 309 East Second Street, Pomona, California 91766, United States.
Peter
P
Oelschlaeger
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry and Materials Science, Northwest University , Xi'an 710127, P. R. China.
Lin
L
Xiao
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry and Materials Science, Northwest University , Xi'an 710127, P. R. China.
Sha-Sha
SS
Nie
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry and Materials Science, Northwest University , Xi'an 710127, P. R. China.
Ke-Wu
KW
Yang
Metallo-β-lactamase; NDM-1; inhibitor; triazolylthioacetamide