Synergistic Antimicrobial and Anticancer Activities of Thiocarbohydrazide‐Based Schiff Base Metal Complexes: Experimental and Theoretical Investigations

ABSTRACT A novel thiocarbohydrazide‐based Schiff base ligand, N ‐(2‐(hydroxyimino)‐1,2‐diphenylethylidene)‐2‐(3‐methoxybenzylidene)hydrazine‐1‐carbothiohydrazide (HBMTmMB), and its transition metal complexes with Mn (II), Fe (II), Co (II), Ni (II), and Cu (II) were synthesized and characterized. The ligand and metal complexes were confirmed using FT‐IR, UV–Vis, NMR, mass spectrometry, elemental analysis, and molar conductance measurements, with magnetic susceptibility indicating octahedral coordination. The Cu (II) complex exhibited the highest antibacterial activity against Escherichia coli (17.3‐mm inhibition zone) and antifungal activity against Candida albicans (15.6‐mm inhibition zone), surpassing the standard antibiotic streptomycin (14.5 mm). Cytotoxicity studies using the brine shrimp lethality assay (BSLA) demonstrated an LC₅₀ of 3.88 × 10 −4 M for the Mn (II) complex and 6.78 × 10 −4 M for the Ni (II) complex, suggesting low toxicity. Anticancer evaluations against MCF‐7 and HeLa cell lines revealed significant cytotoxicity, with Cu (II) and Ni (II) complexes exhibiting IC₅₀ values of 8.9 and 12.3 μM for MCF‐7 and 11.7 and 17.4 μM for HeLa, respectively. The selectivity index (SI) of Cu (II) was 7.70 (MCF‐7) and 5.86 (HeLa), demonstrating preferential cytotoxicity over normal fibroblast cells (L929, IC₅₀ = 68.5 μM). Computational studies, including molecular docking, pharmacophore modeling, and Density Functional Theory (DFT), supported these findings. Docking simulations revealed strong binding affinities, with the Cu (II) complex showing the highest interaction energy (−9.9 kcal/mol) with C. albicans (PDB ID: 5V5Z) and Fe (II) complex showing −8.5 kcal/mol with E. coli (PDB ID: 1HNJ). DFT calculations indicated favorable electronic properties, with a HOMO‐LUMO energy gap of 0.00630164 eV for Cu (II), suggesting high reactivity. These findings highlight the potential of these Schiff base metal complexes as effective antimicrobial and anticancer agents, combining experimental and computational insights to support their therapeutic applications.