Rhodanine as a Potent Scaffold for the Development of Broad Spectrum Metallo-β-lactamase inhibitors

A series of rhodanines was constructed, their Z-configuration was confirmed by small molecule X-ray crystal structures, and their activity against metallo-beta-lactamases (M beta Ls) was measured. The obtained 26 molecules and a thioenolate specifically inhibited the M beta L Ll with an IC50 range of 0.02-1.7 mu M, and compounds 2h-m exhibited broad-spectrum inhibition of the M beta Ls NDM-1, VIM-2, ImiS, and Ll with IC50 values <16 mu M. All inhibitors increased the antimicrobial effect of cefazolin against E. coli cells expressing LI, 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 21 coordinates one or two Zn(II) ions, while the N-phenyl group of the inhibitor enhances its hydrophobic interaction with M beta Ls. These studies demonstrate that the diaryl-substituted rhodanines are good scaffolds for the design of future broad-spectrum inhibitors of M beta Ls.