Design, structural analysis, and biological evaluation of four mononuclear copper(II) complexes as potent urease inhibitors: Insights from experimental and theoretical studies

Abstract

This study develops four copper(II)-based coordination complexes (C1-C4) as potential urease inhibitors through rational ligand design. By combining fluorinated Schiff base ligands with modified bipyridine auxiliary ligands, we systematically investigated how electronic and steric factors influence urease enzyme inhibition. The complexes were synthesized and comprehensively characterized including crystallographic analysis, In each of the four complexes, the central Cu(II) exhibits a five-coordinate geometry, incorporating ONO atoms from the Schiff base ligand and two nitrogen atoms from the auxiliary ligand, which results in a distorted square pyramidal configuration. The biological evaluation identified the complex C1 as exhibiting significantly improved urease inhibitory activity, with an IC₅₀ value of 8.88 ± 1.15 μM, in comparison to the standard reference acetohydroxamic acid, which has an IC₅₀ value of 27.73 ± 2.93 μM. Computational approaches complemented experimental studies to decipher the molecular basis of activity differences among the complexes. On this basis, the structural activity relationship study shows that the urease inhibitory activity of complexes is influenced by electron effect and steric hindrance, providing essential insights for developing new urease inhibitors and advancing their biomedical applications.