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

摘要

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