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

Petrasheuskaya, Tatsiana and Kiss, Márton Attila and Rapta, Peter and Fonay, Csenge and May, Nóra V. and Spengler, Gabriella and Frank, Éva and Enyedy, Éva Anna (2026) Comparative solution study of imidazole-derived thiosemicarbazone complexes: effects of methylation and aromatic conjugation on the redox properties, anticancer, and antibacterial activity. DALTON TRANSACTIONS. ISSN 1477-9226 (In Press)

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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.

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