Fabrication of Copper(II) Coordination Complexes Modulated by Flexible Dicarboxylate Ligands with Notable Urease Inhibitory Performance

Abstract

Copper(II) complexes have attracted increasing attention as potential urease inhibitors owing to their unique coordination versatility, structural diversity, and intrinsic biocompatibility. Urease, a nickel-containing metalloenzyme responsible for the hydrolysis of urea, plays a key role in various pathological processes, making its inhibition a promising therapeutic strategy. In this work, a series of copper(II) complexes were rationally constructed using flexible dicarboxylate ligands as structural modulators to fine-tune molecular geometry and supramolecular organization. The synthesized complexes were comprehensively characterized by infrared and UV–visible spectroscopy, thermogravimetric analysis, and single-crystal X-ray diffraction, which revealed the diverse coordination environments of the copper centers, the variable chelation behaviors of the ligands, and the intricate network of hydrogen bonding and π–π stacking interactions within the crystal lattices. Biological assays demonstrated that the obtained complexes exhibit pronounced and tunable urease inhibitory activities, with several compounds achieving inhibition efficiencies comparable to or exceeding those of known reference inhibitors. Correlation of structural parameters with bioactivity revealed that the degree of ligand flexibility, denticity, and spatial arrangement around the copper center collectively govern enzyme binding affinity and inhibition strength. These findings underscore the importance of molecular design in modulating metal–enzyme interactions and provide new insights into the structure–activity relationships governing copper-based inhibitors. Overall, this study establishes a strategic framework for the development of efficient, adaptable copper(II)-based urease inhibitors, offering both theoretical foundations and experimental references for future exploration in metalloenzyme inhibition and related biomedical applications.