Trypanosoma brucei (T. brucei) and Trypanosoma cruzi (T. cruzi) are causative
agents of parasitic diseases known as human African
trypanosomiasis and Chagas disease, respectively. Together, these
diseases affect 68 million people around the world. Current treatments
are unsatisfactory, frequently associated with intolerable side-effects,
and generally inadequate in treating all stages of disease. In this
paper, we report the discovery of N-ethylurea pyrazoles
that potently and selectively inhibit the viability of T.
brucei and T. cruzi. Sharp and logical SAR
led to the identification of 54 as the best compound,
with an in vitro IC50 of 9 nM and 16 nM
against T. b. brucei and T. cruzi, respectively. Compound 54 demonstrates favorable physicochemical
properties and was efficacious in a murine model of Chagas disease,
leading to undetectable parasitemia within 6 days when CYP metabolism
was inhibited.