Synthesizing a CuII complex of tinidazole to tune the generation of the nitro radical anion in order to strike a balance between efficacy and toxic side effects

Abstract

A monomeric complex of Cu(II) with tinidazole [Cu(tnz)₂Cl₂] was synthesized. The complex decreases the formation of the nitro-radical anion (NO₂˙⁻), which was followed by an enzyme assay involving xanthine oxidase, a model nitro-reductase. It has a binding constant value with DNA comparable to that of tinidazole. In addition to the drug efficacy of the nitro radical anion, it also has neurotoxic side effects; so it is essential to control its formation to an optimum, sufficient for bringing about cytotoxic activity on disease causing microbes but avoiding excess that could make it neurotoxic. If this is achieved through modification of the 5-nitroimidazole moiety then too much NO₂˙⁻ would not be generated, implying that the chances of the drug causing any harm to the host due to toxic side effects could be reduced. However, with decreased NO₂˙⁻ formation, in an effort to decrease complications, a certain amount of therapeutic efficacy would be compromised. Therefore, the biological activity of tinidazole and its modified form, a monomeric complex, was investigated to see how the latter compares with tinidazole under comparable conditions. Studies revealed that, in spite of decreased NO₂˙⁻ formation, the complex showed similar activity to that of tinidazole on two bacterial strains and an amoeba strain, implying that it has other attributes, not known for 5-nitroimidazoles, that enable it to match the efficacy of tinidazole. The study suggests that there is a substantial decrease in NO₂˙⁻ due to the formation of the tinidazole complex, meaning that the toxic side effects are likely to be reduced which is an advantage as it would improve the therapeutic index.