Structural Insights and Bioactivity Correlations of Heteroleptic Zn(II)/Cd(II) Complexes: Experimental Characterization, Theoretical Modelling, and Evaluation of Antimicrobial, Anticancer, and Lipase Inhibitory Potentials.

Driven by the critical need for new therapeutic agents, and building upon recognized biological relevance of hydroxamic acids, our rationale posits that integrating distinct ligands can precisely modulate a metal complex’s properties to achieve targeted biological activity. Two new mixed ligand complexes, [ZnCl(L)(1,10-phen)] (1) and [Cd(L)(1,10-phen)].H2O (2) {where, L = 1-naphthaleneacetohydroxamate (1-NaphAcH, C11H9CONHO) and 1,10-phen = 1,10-phenanthroline (C12H8N2)} has been synthesized by reacting ZnCl2 and CdCl2 (anhydrous) with ligand potassium 1-naphthaleneacetohydroxamate (C11H9CONHOK) (L) as primary ligand and 1,10-phenanthroline as secondary ligand. Complexes were characterized by physicochemical, spectroscopic (FTIR, 1H, 13C NMR, UV-Visible), Mass, Thermogravimetric analysis (TGA), Cyclic Voltammetry (CV) and theoretical (DFT) affirmed their distorted square pyramidal geometries and elucidated their electronic structure, revealing enhanced stability. Critically, these complexes demonstrated significant broad-spectrum antibacterial efficacy, comparable to azithromycin, against bacterial strains S. aureus, S. typhi, S. flexneri, and P. aeruginosa. Furthermore, both complexes exhibited potent cytotoxicity against L20B as well as Rhabdomyosarcoma (RD) cancer cells and IC50 values were determined substantiated by in-silico DNA binding studies elucidating probable mechanism of action. The complexes were evaluated for their in-vitro inhibitory activity against Amano Lipase PS enzyme and demonstrated efficient lipase inhibition. The stability of coordination complexes was evaluated in biological media using UV-visible spectrophotometry pertinent to their antibacterial, anticancer, and lipase enzyme inhibition activities. Molecular docking simulations corroborated these in vitro findings, demonstrating efficient docking scores. Furthermore, Normal Mode Analysis (NMA) revealed a pronounced metal-dependent modulation of protein dynamics, wherein coordination to Zn(II) and Cd(II) progressively suppresses low-frequency collective motions critical for biological function. Notably, the Cd(II) complex induces the strongest conformational stabilization and residue coupling, providing a mechanistic basis for its enhanced antibacterial activity. These findings underscore the profound potential of rational mixed-ligand design to transform metal ions into versatile, highly active biological agents for addressing pressing challenges in antimicrobial resistance, cancer therapy and lipase inhibition.