Drug Repositionings in the Near Future;
Rhodanine as a Potent Scaffold for the Development of Broad-Spectrum Metallo-β-lactamase Inhibitors
Yang Xiang†§, Cheng Chen†§, Wen-Ming Wang†, Li-Wei Xu†, Ke-Wu Yang*† 
, Peter Oelschlaeger‡ , and Yuan He*†
† Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Chemical Biology Innovation Laboratory, College of Chemistry and Materials Science, Northwest University , Xi’an 710127 , P. R. China
‡ Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, 309 East Second Street, Pomona , California 91766 , United States
ACS Med. Chem. Lett., Article ASAP
DOI: 10.1021/acsmedchemlett.7b00548
Publication Date (Web): March 22, 2018
Copyright © 2018 American Chemical Society
Abstract
A series of rhodanines was constructed, their Z-configuration was confirmed by small molecule X-ray crystal structures, and their activity against metallo-β-lactamases (MβLs) was measured. The obtained 26 molecules and a thioenolate specifically inhibited the MβL L1 with an IC50 range of 0.02–1.7 μM, and compounds 2h–m exhibited broad-spectrum inhibition of the MβLs NDM-1, VIM-2, ImiS, and L1 with IC50 values <16 μM. All inhibitors increased the antimicrobial effect of cefazolin against E. coli cells expressing L1, resulting in a 2–8-fold reduction in MIC. Docking studies suggested that the nitro (NDM-1, CphA, and L1) or carboxyl group (VIM-2) of 2l coordinates one or two Zn(II) ions, while the N-phenyl group of the inhibitor enhances its hydrophobic interaction with MβLs. These studies demonstrate that the diaryl-substituted rhodanines are good scaffolds for the design of future broad-spectrum inhibitors of MβLs.
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmedchemlett.7b00548.
- Synthesis and characterization of compounds, X-ray crystallography, methods for enzyme expression and purification, rhodanine stability assays, inhibition kinetic studies, MIC assays including pH monitoring, cytotoxicity assay, docking studies, and graphical views of MβL/2l complexes (PDF)
- Spectra (PDF)
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