Comparative solution study of imidazole-derived thiosemicarbazone complexes: effects of methylation and aromatic conjugation on the redox properties, anticancer, and antibacterial activity

Abstract

A series of imidazole-based thiosemicarbazones (TSCs) was developed, and their metal complexation behavior was comprehensively investigated in solution. In addition, the structures of four ligands and four corresponding complexes were determined by single-crystal X-ray diffraction, revealing that Cu(II) and Fe(III) complexes adopt coordination through the (N,N,S) donor set. Lipophilicity, acid–base and complex formation equilibria with Cu(II), Fe(II/III), and Ni(II) were characterized using pH-potentiometry, UV-visible and electron paramagnetic resonance spectroscopy methods. Based on the solution equilibrium data, the imidazole-TSCs exist predominantly in their neutral form at physiological pH (7.4), and exhibit a stronger affinity for Cu(II) than for Fe(II), Fe(III) or Ni(II). They form mono-ligand complexes with all of these metals, and additionally tetranuclear complexes with Cu(II). The electrochemical properties of the Cu(II) complexes were characterized by cyclic voltammetry and UV-visible spectroelectrochemistry, revealing all Cu(II) complexes of imidazole-TSCs follow an electrochemical dual-pathway square scheme. The anticancer activity of imidazole-TSC derivatives was evaluated against the human cancer cell lines Colo205 and the doxorubicin-resistant Colo320. Coordination of imidazole-TSC derivatives to Cu(II) or Ni(II) markedly enhanced their anticancer activity against Colo205 and Colo320 cells. Among the compounds tested, Me₂-imidazole-TSC demonstrated the greatest potency, while the benzimidazole-TSC complex also exhibited pronounced activity. Methyl substitution and aromatic conjugation were found to substantially improve the cytotoxic effect.