Molecular Docking, DFT, and Structural Characterization of Cr(III), Mn(II), and Fe(III) Mixed-Ligand Complexes With Nifuroxazide and 4-Chloro-Pyridine-2-Carboxylic Acid: New Perspectives on Antibacterial and Anti-Inflammatory Activity.

The development of metal-based therapeutics offers a promising strategy to overcome antimicrobial resistance and enhance anti-inflammatory efficacy. In this study, three new mixed-ligand complexes of Cr(III), Mn(II), and Fe(III) with nifuroxazide (NF) and 4-chloro-pyridine-2-carboxylic acid (CP) were synthesized and comprehensively characterized. Spectroscopic, magnetic, and thermal analyses, supported by DFT calculations, confirmed octahedral coordination geometries, with CrPCNF and FePCNF behaving as 1:1 electrolytes (Λm = 40.52 and 40.55 Ω-1cm2mol-1, respectively), while MnPCNF (Λm = 11.32  Ω-1cm2mol-1) was non-electrolytic. Density functional theory revealed reduced HOMO-LUMO energy gaps and high electrophilicity indices for MnPCNF (3.14 eV; ω = 19.44) and FePCNF (2.71 eV; ω = 20.53), indicating enhanced chemical reactivity relative to the free ligands. Biological evaluation demonstrated a pronounced improvement in antibacterial, antifungal, and anti-inflammatory activities upon metal complexation. Notably, the FePCNF complex exhibited the highest antibacterial activity (31.0 mm against Bacillus subtilis and 30 mm against Klebsiella pneumoniae; MIC = 80 µM), superior antifungal efficacy (20 mm inhibition zones; MIC = 100 µM), and the strongest anti-inflammatory response (25.07% inhibition at 500 µM; IC50 = 71.23 µM). Molecular docking against Escherichia coli FabH and COX-2 enzymes corroborated the experimental results, with FePCNF showing the most favorable binding affinities (-8.90 and -9.50 kcal mol-1, respectively). Overall, these findings proposed that the Fe(III) mixed-ligand complex might be a promising multifunctional candidate drug for further development as an antimicrobial and anti-inflammatory agent.