Hit-to-Lead Optimization of a Novel Class of Potent, Broad-Spectrum Trypanosomacides

The parasitic trypanosomes Trypanosoma brucei and T. cruzi are responsible for
significant human suffering in the form of human African trypanosomiasis
(HAT) and Chagas disease. Drugs currently available to treat these
neglected diseases leave much to be desired. Herein we report optimization
of a novel class of N-(2-(2-phenylthiazol-4-yl)­ethyl)­amides,
carbamates, and ureas, which rapidly, selectively, and potently kill
both species of trypanosome. The mode of action of these compounds
is unknown but does not involve CYP51 inhibition. They do, however,
exhibit clear structure–activity relationships, consistent
across both trypanosome species. Favorable physicochemical parameters
place the best compounds in CNS drug-like chemical space but, as a
class, they exhibit poor metabolic stability. One of the best compounds
(64a) cleared all signs of T. cruzi infection in mice when CYP metabolism was inhibited, with sterile
cure achieved in one mouse. This family of compounds thus shows significant
promise for trypanosomiasis drug discovery.