A ZnII complex of ornidazole with decreased nitro radical anions that is still highly active on Entamoeba histolytica

Abstract

A monomeric complex of Zn^II with ornidazole [Zn(Onz)₂Cl₂] decreases formation of the nitro-radical anion (R–NO₂˙⁻), and this is realized by recording it in an enzyme assay using xanthine oxidase, which is a model nitro-reductase. Although the formation of R–NO₂˙⁻ is essential for drug action, as it is also associated with neurotoxic side effects, it is imperative to control its generation in order to avoid excess presence. With a decrease in R–NO₂˙⁻, while the neurotoxic side effects should decrease, it can be expected that a compromise with regard to therapeutic efficacy will be seen since the complex will be less active in the free radical pathway. Since R–NO₂˙⁻ is crucial for the functioning of 5-nitroimidazoles, we attempted to find out if its biological activity is affected in any way in our effort to control its formation. For this purpose, Entamoeba histolytica (HM1:IMS Strain) was chosen as a biological target to realize the performance of the complex with respect to ornidazole (R–NO₂). The experiments revealed that the complex not only compares well with ornidazole, but in fact, under longer exposure times, it also performs better than it. This efficacy of the complex was seen despite a decrease in R–NO₂˙⁻, as identified by an enzyme assay, and this was probably due to certain attributes of the complex formation that are not known for ornidazole. These attributes outweigh any loss in efficacy in the free radical pathway following complex formation. This is certainly an advantage of complex formation and helps to improve the therapeutic index. This study has attempted to look at some of the possible reasons why the complex performs better than ornidazole. One reason is its ability to bind to DNA better than ornidazole does, and this can be understood by following the interaction of ornidazole and its Zn(II) complex with calf-thymus DNA using cyclic voltammetry. Therefore, this study showed that despite a decrease in R–NO₂˙⁻, the complex does not compromise its efficacy, and this was examined using a biological target. In addition, the complex is likely to have less toxic side effects on the host of the disease-causing microbes.