Abstract
A type II Platelet-Derived Growth Factor Receptor Alpha (PDGFRA) human kinase inhibitor GSK190937, with antiplasmodium activity against asexual blood stage parasites (PfNF54 IC(50) = 0.22 μM) was identified from the Kinase Chemogenomics Set, a collection of narrow-spectrum human kinase inhibitors. Medicinal chemistry progression of the hit focused on improving potency, selectivity, and ADME properties, leading to compounds 20, 23, and 29 with improved microsomal metabolic stability and asexual blood stage antiplasmodium activity. Mechanism of action studies showed that this series inhibits hemozoin formation, killing late-stage trophozoites.