title: Azolylthioacetamide: A Highly Promising Scaffold for the Development of Metallo-β-lactamase Inhibitors.
abstract: A new scaffold, azolylthioacetamide, was constructed and assayed against metallo-β-lactamases (MβLs). The obtained molecules specifically inhibited MβL ImiS, and 1c was found to be the most potent inhibitor, with a K i = 1.2 μM 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 1a, 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.
authors.affiliation: 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.
authors.forename: Shao-Kang
authors.initials: SK
authors.lastname: Yang
authors.affiliation: Department of Biological Sciences, California State Polytechnic University , 3801 West Temple Avenue, Pomona, California 91768, United States.
authors.forename: Joon S
authors.initials: JS
authors.lastname: Kang
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences , 309 East Second Street, Pomona, California 91766, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Oelschlaeger
authors.affiliation: 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.
authors.forename: Ke-Wu
authors.initials: KW
authors.lastname: Yang
keywords: Antibiotic resistance; ImiS; azolylthioacetamide; inhibitor; metallo-β-lactamase; subclass B2