Development of a 2,4-Diaminothiazole Series for the Treatment of Human African Trypanosomiasis Highlights the Importance of Static–Cidal Screening of Analogues

While treatment options for human African trypanosomiasis
(HAT)
have improved significantly, there is still a need for new drugs with
eradication now a realistic possibility. Here, we report the development
of 2,4-diaminothiazoles that demonstrate significant potency against Trypanosoma brucei, the causative agent of HAT. Using
phenotypic screening to guide structure–activity relationships,
potent drug-like inhibitors were developed. Proof of concept was established
in an animal model of the hemolymphatic stage of HAT. To treat the
meningoencephalitic stage of infection, compounds were optimized for
pharmacokinetic properties, including blood–brain barrier penetration.
However, in vivo efficacy was not achieved, in part due to compounds
evolving from a cytocidal to a cytostatic mechanism of action. Subsequent
studies identified a nonessential kinase involved in the inositol
biosynthesis pathway as the molecular target of these cytostatic compounds.
These studies highlight the need for cytocidal drugs for the treatment
of HAT and the importance of static–cidal screening of analogues.