Metronidazole Interaction with Cu²⁺ and Zn²⁺: Speciation Study in Aqueous Solution and Biological Activity Evaluation

Metronidazole (2-methyl-5-nitro-1H-imidazole-1-ethanol, MNZ) is a well-known and widely used drug for its excellent activity against various anaerobic bacteria and protozoa. The purpose of this study is to elucidate the ability of MNZ to form metal complexes with Cu²⁺ and Zn²⁺ and to demonstrate that complexation increases its bioactivity profile against different pathogenic microorganisms. The interaction of MNZ with Cu²⁺ and Zn²⁺ was investigated in NaCl aqueous solution under different conditions of temperature (15, 25, and 37 °C) and ionic strength (0.15, 0.5, and 1 mol L^-1) by potentiometric and spectrophotometric titrations. The obtained speciation models include two species for the Cu²⁺-containing system, namely, CuL and CuL₂, and three species for the Zn²⁺-containing system, namely, ZnLH, ZnL, and ZnLOH. The formation constants of the species were calculated and their dependence on temperature and ionic strength evaluated. Comparison of the sequestering ability of MNZ under physiological conditions revealed a capacity toward Cu²⁺ higher than that toward Zn²⁺. A simulation under the same conditions also showed a significant percentage of the Cu²⁺-MNZ species. The biological assessments highlighted that the complexation of MNZ with Cu²⁺ has a relevant impact on the potency of the drug against two Trypanosoma spp. (i.e., T. b. brucei and T. b. rhodesiense) and one gram-(-) bacterial species (i.e., Escherichia coli). It is noteworthy that the increased potency upon complexation with Cu²⁺ did not result in cytotoxicity against MRC-5 human fetal lung fibroblasts and primary peritoneal mouse macrophages.