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 IC₅₀ 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.