Green Synthesis of New Water‐Soluble Nickel (II) and Copper (II) Mixed‐Ligand Complexes: Characterization, DFT, In Vitro Biological Evaluation, and COVID‐19 Molecular Docking

ABSTRACT This study presents the synthesis, characterization, and bioevaluation of novel water‐soluble nickel (NiMNPSCA) and copper (CuMNPSCA) mixed‐ligand complexes. The complexes were synthesized in aqueous media using Ni (II) or Cu (II), sodium salicylate (SCA), and a Schiff base derived from 2‐hydroxy naphthaldehyde (MNP). Comprehensive characterization was achieved using UV–vis, IR spectroscopy, mass spectrometry, elemental analysis, and thermal and magnetic techniques. Both complexes exhibited exceptional thermal stability (melting points > 300°C), water solubility, and 1:1 electrolyte behavior. Structurally, NiMNPSCA adopts a tetrahedral geometry, while CuMNPSCA features an octahedral arrangement. Quantum chemical analyses revealed a narrower energy gap ( ΔE = 3.06 eV) and a higher electrophilicity index ( ω = 9.66) for CuMNPSCA, suggesting superior chemical reactivity and biological potential. Both complexes demonstrated significantly enhanced antibacterial, antifungal, and anti‐inflammatory activities compared to their free ligands, with CuMNPSCA showing efficacy comparable to standard agents in both antimicrobial and anti‐inflammatory applications. Notably, CuMNPSCA exhibited potent anti‐inflammatory activity, achieving the highest inhibition rate and an IC 50 value competitive with ibuprofen. Molecular docking studies reinforced these findings, highlighting the strong binding affinities of CuMNPSCA to dihydropteroate synthase (DHPS, PDB ID: 5JQ9; −8.00 kcal/mol), cyclooxygenase (COX, PDB ID: 6COX; −9.80 kcal/mol), and the SARS‐CoV‐2 main protease (Mpro, PDB ID: 6LU7; −7.60 kcal/mol). Detailed interaction analysis revealed that metal coordination significantly enhanced the complexes' stability and binding efficacy through hydrogen bonds, π‐π stacking, and π‐cation interactions. This work positions NiMNPSCA and CuMNPSCA as highly promising candidates for antimicrobial, antifungal, and anti‐inflammatory drug development, with CuMNPSCA emerging as a standout compound with strong therapeutic potential. Its multifaceted bioactivity, combined with robust structural stability and reactivity, underscores its potential as a versatile therapeutic agent, particularly in antimicrobial resistance and anti‐COVID‐19 strategies.