The Design and Synthesis of Potent and Selective Inhibitors of Trypanosoma brucei Glycogen Synthase Kinase 3 for the Treatment of Human African Trypanosomiasis

Glycogen
synthase kinase 3 (GSK3) is a genetically validated drug
target for human African trypanosomiasis (HAT), also called African
sleeping sickness. We report the synthesis and biological evaluation
of aminopyrazole derivatives as Trypanosoma brucei GSK3 short inhibitors. Low nanomolar inhibitors, which had high
selectivity over the off-target human CDK2 and good selectivity over
human GSK3β enzyme, have been prepared. These potent kinase
inhibitors demonstrated low micromolar levels of inhibition of the Trypanosoma brucei brucei parasite grown in culture.