Contribution of copper(II) and zinc(II) to the electrochemical and biological properties of 5-nitroimidazole coordination compounds. An experimental and theoretical approach.

Coordination compounds of copper(II) and zinc(II) with the 5-nitroimidazole derivatives 1-(2-chloroethyl)-2-methyl-5-nitroimidazole (cenz) and 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole (onz) have shown antiparasitic activity against Toxoplasma gondii. This study combines electrochemical and theoretical approaches to evaluate the role of the metal ion in the formation and stability of redox species potentially involved in their mechanism of action. The free ligands exhibited oxidation and reduction peaks corresponding to the formation of nitro radical anion and hydroxylamine species, associated with their biological activity. In the coordination compounds, the metal ion influenced these processes by different mechanisms. Theoretical analysis revealed that the nitro radical anion can be stabilized by intramolecular hydrogen bonding or by lone pair···π hole interactions. In the copper(II) complexes, these interactions were further enhanced by a redox-driven structural rearrangement in which the coordination geometry shifts from distorted tetrahedral to trigonal planar upon CuII/CuI reduction. This geometrical change promotes stabilization of the nitro radical and facilitates redox cycling, which may contribute to antiparasitic activity. In contrast, the zinc(II) complexes maintain a regular tetrahedral geometry and present an intramolecular redox mechanism, where the nitro group is reduced via a transient state. To explore their potential anticancer activity, in vitro assays were conducted against HeLa, HCT-15 and A549 human cancer cell lines and L929 healthy fibroblast. Additionally acute toxicity studies were performed. The results support the potential of these coordination compounds as antiparasitic and anticancer agents, highlighting the key role of metal-induced structural and electronic effects into modulating biological activity.