Sustainable synthesis of bivalent Ni²⁺, Co²⁺, and Cu²⁺ Schiff base complexes <i>via</i> ball milling as a green approach: A study of spectroscopic characterization, cyclic voltammetry, bioactivity, DFT analysis, SAR,

The synthesis of 3-(2-hydroxybenzylidene)-N-(benzothiazol-2-yl)hydrazine-3-oxopropanamide (H2BT) presents a novel approach to chelation by the incorporation of carbonyl and benzothiazole groups, which significantly enhances binding efficiency and selectivity toward transition metal ions such as Ni 2 ⁺, Co 2 ⁺, and Cu 2 ⁺. This work uniquely employs a ball milling technique for the formation of Schiff base solid chelates, positioning it as a more environmentally friendly alternative to conventional solvent-based methods. A comprehensive characterization of the synthesized compounds was conducted using various analytical techniques, including thermal analyses (TG, DTG),= elemental analyses ( 1 H, 13 C-NMR Infrared (FTIR), electron spin resonance (ESR), UV-visible, Energy dispersive X-ray (EDX), powder X-ray diffraction (XRD), Mass spectra (MS)), and Scan electron microscope (SEM), validating the structural integrity and composition of the ligand and its metal complexes. Additionally, quantum-mechanical investigations employing density functional theory (DFT) provide insights into the electronic properties of the prepared compounds. The bioactivity of H 2 BT and its metal chelates was systematically evaluated using standard assays and assessing cytotoxicity, antioxidant activity, antibacterial effects, DNA-binding capacity, and erythrocyte hemolysis. The binding affinities of the complexes were further analyzed using the Molecular Operating Environment (MOE) software, referencing the crystallographic structure of the BCL2 receptor-bound ligand (PDB: 2w3l). To elucidate the complexation behavior in solution, cyclic voltammetry was performed at 291.15 K with copper (II) ions in a Dimethyl sulfoxide (DMSO)-water mixture, revealing critical electrochemical insights. Overall, this study not only enriches the understanding of H 2 BT as a ligand but also highlights its potential applications in bioinorganic chemistry, drug development, and catalysis, underscoring the innovation in utilizing a green synthesis approach for metal coordination chemistry.