Antiplasmodial dihetarylthioethers target the coenzyme A synthesis pathway in Plasmodium falciparum erythrocytic stages.

摘要: Malaria is a widespread infectious disease that threatens large proportion of the population in tropical and subtropical areas. Given emerging resistance against current standard anti-malaria chemotherapeutics, development alternative drugs urgently needed. New anti-malarials representing chemotypes unrelated to currently used have an increased potential for displaying novel mechanisms action thus exhibit low risk cross-resistance established drugs. Phenotypic screening small library (32 kinase-inhibitor analogs) Plasmodium falciparum NF54-luc asexual erythrocytic stage parasites identified diarylthioether structurally registered Hit expansion led series which most potent congener displayed nanomolar antiparasitic activity (IC50 = 39 nM, 3D7 strain). Structure–activity relationship analysis revealed thieno[2,3-d]pyrimidine on one side thioether linkage as prerequisite antiplasmodial activity. Within series, oxazole derivative KuWei173 showed high potency (IC50 = 75 nM; strain), good solubility aqueous solvents (1.33 mM), and >100-fold selectivity toward human cell lines. Rescue experiments inhibition plasmodial coenzyme A synthesis possible mode this compound class. The class bishetarylthioethers reported here has been shown interfere with synthesis, mechanism not yet exploited anti-malarial displays double-digit activity, lines, drug likeness, represents promising chemical starting point further development.