AbstractNew drugs are urgently needed for the treatment of tropical parasitic diseases such as leishmaniasis and human African trypanosomiasis (HAT). This work involved a high‐throughput screen of a focussed kinase set of ∼3400 compounds to identify potent and parasite‐selective inhibitors of an enzymatic Leishmania CRK3–cyclin 6 complex. The aim of this study is to provide chemical validation that Leishmania CRK3–CYC6 is a drug target. Eight hit series were identified, of which four were followed up. The optimisation of these series using classical SAR studies afforded low‐nanomolar CRK3 inhibitors with significant selectivity over the closely related human cyclin dependent kinase CDK2.