From Structure to Function: COX‐Selective Anti‐Inflammatory Activity of Cu(II) and Zn(II) Hydrazone Complexes

Hydrazone‐based ligands constitute multifunctional pharmacophores owing to their flexible coordination modes and tunable electronic properties. Upon metal complexation, these features modulate physicochemical characteristics and biological responses, enabling the development of metal‐based therapeutics. This study reports the rational design, synthesis, structural characterization, and anti‐inflammatory evaluation of a series of hydrazone ligands and their Cu(II) and Zn(II) complexes. Spectroscopic and crystallographic analyses confirmed tridentate coordination through azomethine nitrogen and carbonyl oxygen donors, leading to distorted octahedral geometries around the metal centers. In vitro cyclooxygenase inhibition assays showed that metal coordination significantly enhanced anti‐inflammatory activity relative to the free ligands. The Cu(II) complexes Cu(acbh) 2 ( 3 ) and Cu(bcbh) 2 ( 5 ), along with the Zn(II) complex Zn(bcbh) 2 ( 6 ), exhibited notable COX‐2 selectivity compared to the reference drug celecoxib. Among all compounds, complex 6 emerged as the most potent dual COX‐1/COX‐2 inhibitor, displaying a COX‐2 IC 50 value of 0.41 µM and a selectivity index of 307.32, indicating potential as a broad‐spectrum anti‐inflammatory agent. Molecular docking studies supported these results, revealing favorable binding energies and stable interactions of the metal complexes within COX active sites. Overall, these findings emphasize the role of metal coordination in enhancing enzyme binding and biological activity.