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.