Trypanosoma cruzi: efficacy of the 2-substituted, 5-nitroimidazoles, MK-436 and L634,549, in tissue culture and mice.

Experimental studies were undertaken in tissue culture and mice infected with a cloned derivative of Trypanosoma cruzi, Y strain to determine the efficacy of two 2-substituted 5-nitroimidazole compounds, MK-436 and L634,549. The use of an X-irradiated myoblast culture system proved better than a conventional fibroblast culture for assaying the activity of compounds against intracellular parasite stages. MK-436 showed activity against amastigotes at a level of 25 micrograms/ml and L634,549 a dihydroxy metabolite of MK-436 showed activity 2 micrograms/ml. Neither compound caused morphological damage to the host cells at levels tested (250 micrograms/ml). By contrast, nifurtimox, which was active at 2 micrograms/ml, caused significant host cell damage at 100 micrograms/ml. In mice, studies in the chronic infection showed that MK-436 was curative at a level of 30 mg/kg if given daily for 20 days. Neither nifurtimox nor benznidazole were fully curative when given at a level of 100 mg/kg daily for 20 days. These studies showed that administration of MK-436 with a suitable solvent, PEG 400, enhanced its efficacy fourfold, and that efficacy was also enhanced by increasing the treatment interval. Since MK-436 showed better efficacy in chronic rodent infections than either nifurtimox or benznidazole, such compounds should be evaluated for efficacy in human Chagas' disease.