Repositioning of a Diaminothiazole Series Confirmed to Target the Cyclin-Dependent Kinase CRK12 for Use in the Treatment of African Animal Trypanosomiasis br

African animal trypanosomiasis or nagana, caused principally by infection of the protozoan parasitesTrypanosomacongolenseandTrypanosoma vivax,is a major problem in cattle andother livestocks in sub-Saharan Africa. Current treatments arethreatened by the emergence of drug resistance and there is anurgent need for new, effective drugs. Here, we report therepositioning of a compound series initially developed for thetreatment of human African trypanosomiasis. A medicinal chemistry program, focused on deriving more soluble analogues, led todevelopment of a lead compound capable of curing cattle infected with bothT. congolenseandT. vivaxvia intravenous dosing.Further optimization has the potential to yield a single-dose intramuscular treatment for this disease. Comprehensive mode of actionstudies revealed that the molecular target of this promising compound and related analogues is the cyclin-dependent kinase CRK12