Metronidazole Interaction with Cu(2+) and Zn(2+): 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 Cu(2+) and Zn(2+) and to demonstrate that complexation increases its bioactivity profile against different pathogenic microorganisms. The interaction of MNZ with Cu(2+) and Zn(2+) was investigated in NaCl aqueous solution under different conditions of temperature (15, 25, and 37 degrees 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 Cu(2+)-containing system, namely, CuL and CuL(2), and three species for the Zn(2+)-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 Cu(2+) higher than that toward Zn(2+). A simulation under the same conditions also showed a significant percentage of the Cu(2+)-MNZ species. The biological assessments highlighted that the complexation of MNZ with Cu(2+) 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 Cu(2+) did not result in cytotoxicity against MRC-5 human fetal lung fibroblasts and primary peritoneal mouse macrophages.