Discovery of Potent Antimalarial Type II Kinase Inhibitors with Selectivity over Human Kinases

While
progress has been made in the effort to eradicate
malaria,
the disease remains a significant threat to global health. Acquired
resistance to frontline treatments is emerging in Africa, urging a
need for the development of novel antimalarial agents. Repurposing
human kinase inhibitors provides a potential expedited route given
the availability of a diverse array of kinase-targeting drugs that
are approved or in clinical trials. Phenotypic screening of a library
of type II human kinase inhibitors identified compound 1 as a lead antimalarial, which was initially developed to target
human ephrin type A receptor 2 (EphA2). Here, we report a structure–activity
relationship study and lead optimization of compound 1, which led to compound 33, with improved antimalarial
activity and selectivity.