biostudies-literatureWang LNational Institute of Allergy and Infectious DiseasesNIAID NIH HHS1460-1480https://www.ebi.ac.uk/biostudies/studies/S-EPMC10950204biostudies-literatureUnknown67(2)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 <b>1</b> 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 <b>1</b>, which led to compound <b>33,</b> with improved antimalarial activity and selectivity.Journal of medicinal chemistryDiscovery of Potent Antimalarial Type II Kinase Inhibitors with Selectivity over Human Kinases.PMC10950204AI172066R01 AI152533R01 AI169892R01 AI172066Calla JNardella FRocamora FLaureano De Souza MCharlton JTBohmer MJWang JChakrabarti DWang LGray NSSchindler KACooper RAMontejo LTreat MWinzeler EAChakrabarti RMittal NTumwebaze PKRosenthal PJfalseDiscovery 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 <b>1</b> 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 <b>1</b>, which led to compound <b>33,</b> with improved antimalarial activity and selectivity.2024-01-01T00:00:00Z2024 Jan2025-04-04T02:09:19.458Z2025-04-04T02:09:19.458ZS-EPMC109502043821425410.1021/acs.jmedchem.3c02046