Characterization of a melamino nitroheterocycle as a potential lead for the treatment of human African trypanosomiasis

This paper reports an evaluation of a melamine-nitroheterocycle, a potential lead for further development as an agent against human African trypanosomiasis (HAT). Studies on its efficacy, physicochemical and biopharmaceutical properties and potential for toxicity are described. The compound had previously been shown to possess exceptional activity against Trypanosoma brucei in in vitro assays, comparable to that of melarsoprol. Here, we demonstrate that the compound was also curative in the stringent acute mouse model T. b. rhodesiense STIB 900, when given intraperitoneally at 40 mg/kg. Nevertheless, activity was only moderate when the oral route was used and no cure was obtained when the compound was tested in a stage 2 rodent model of infection. Genotoxic profiling revealed that the compound induces DNA damage, in a mechanism apparently independent from nitro-reduction, and involving introduction of base-pair substitutions (Ames test), possibly caused by oxidative damage of the DNA (Comet test). No significant genotoxicity was observed at the chromosome level (micronucleus assay). The lack of suitable properties for oral and central nervous system uptake and the genotoxic liabilities prevent the progression of this melamine-nitroheterocycle as a drug candidate for HAT. Further modification of the compound is required to improve the pharmacokinetic properties of the molecule and to separate the trypanocidal activity from the toxic potential