Characterization of a Melamino Nitroheterocycle as a Potential Lead for the Treatment of Human African Trypanosomiasis

Abstract

dThis paper reports an evaluation of a melamino 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 previously had been shown to possess exceptional activity against Trypanosoma brucei in in vitro assays comparable to that of melarsoprol. Here, we demonstrate that the compound also was curative in the stringent acute mouse model T. brucei rhodesiense STIB 900 when given intraperitoneally at 40 mg/kg of body weight. 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 by a mechanism apparently independent from nitroreduction and involving the 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.

Unravelling the role of SNM1 in the DNA repair system of Trypanosoma brucei

“…One way to facilitate the development of new drugs targeting HAT is to better understand the mechanism of action of existing treatments with the properties that underlie parasite selectivity incorporated into the development of new trypanocidal agents. For example, melamine rings have been incorporated into several compounds to exploit the substrate specificity displayed by the P2 adenosine transporter, a permease implicated in the uptake of pentamidine and melarsoprol (Stewart et al ., ; Baliani et al ., ; Chollet et al ., ; Klee et al ., ; Capes et al ., ; Giordani et al ., ). Similarly, a parasite nitroreductase (NTR), an enzyme responsible for the activation of nifurtimox (Wilkinson et al ., ; Hall et al ., ), has been used to screen nitroaromatic libraries for anti‐ T. brucei properties (Bot et al ., 2010; 2013; Hall et al ., 2010; 2012; Hu et al ., ; Papadopoulou et al ., 2011; 2012; 2013).…”

Further Investigations of Nitroheterocyclic Compounds as Potential Antikinetoplastid Drug Candidates

“…In addition, when 20 mg/kg of this compound was administered daily by the intraperitoneal route for 4 consecutive days to mice infected with T. b. brucei , a curative effect was observed [ 187 , 188 ]. In another study [ 189 ], when the dose was increased to 40 mg/kg/day, mice infected with T. b. rhodesiense were also cured. These authors also observed that oral treatment with 100 mg/kg for 4 days gave rise to moderate activity, whereas 10 doses of 50 mg/kg given intraperitoneally did not provide cure in a stage 2 rodent model of infection.…”

“…The genotoxicity observed in the Ames test is due to activation by bacterial type I NTR (similar to the enzymes found in trypanosomes)—a reaction that cannot be conducted by the mammalian type II NTR. Therefore, nitroheterocyclic compounds should be deeply examined, because they could be functional and non-genotoxic [ 189 , 191 , 204 ].…”