Synthesis, structural elucidation, biological, DFT, molecular docking investigation of new mixed-ligand Ni(II) and Cu(II) complexes derived from Schiff base and bromhexine

Abstract

The emergence of multidrug-resistant microbial strains necessitates the design of new coordination compounds with enhanced biological activity. In this study, two new mixed-ligand Ni(II) and Cu(II) complexes were synthesized from Bromhexine (BR) and a Schiff base (SB) derived from 2-hydroxy-1-naphthaldehyde and p-toluidine, aiming to explore their structural, electronic, and biological properties. Comprehensive characterization using elemental analysis, FT-IR, UV–Vis, mass spectrometry, magnetic, conductivity, and thermal measurements confirmed the formation of [Ni(BR)(SB)]Cl and [Cu(BR)(SB)(Cl)(H₂O)] complexes with tetrahedral and distorted octahedral geometries, respectively. The Ni(II) complex behaved as a 1:1 electrolyte, while the Cu(II) complex was non-electrolytic, indicating different coordination environments. Thermal analysis corroborated the absence of hydration water and the presence of one coordinated water molecule in CuBRSB. Density Functional Theory (DFT) calculations revealed that NiBRSB has the lowest HOMO-LUMO energy gap (2.55 eV), highest softness (0.39), and strongest nucleophilicity (1.98), consistent with its superior reactivity. Biological assays demonstrated markedly enhanced antibacterial and antifungal activities for both complexes, particularly NiBRSB, which showed inhibition zones up to 25.4 mm against Klebsiella pneumoniae and 24.4 mm against Candida albicans. Molecular docking against the bacterial target FabH-CoA (PDB ID: 1HNJ) supported these results, revealing strong binding affinities (−9.20 kcal mol⁻¹) and key hydrogen-bond interactions.