Tambjamines as Fast-Acting Multistage Antimalarials.

Abstract

Well-tolerated and novel antimalarials that can combat multiple stages of the parasite life cycle are desirable but challenging to discover and develop. Herein, we report results for natural product-inspired novel tambjamine antimalarials. We show that they are potent against liver, asexual erythrocytic, and sexual erythrocytic parasite life cycle stages. Notably, our lead candidate(KAR425) displays excellent oral efficacy with complete clearance of parasites within 72 h of treatment in the humanized(NOD-scid) mouse model at 50 mg/kg × 4 days. Profiling of compounddemonstrated a fastkilling profile. In addition, several other tambjamine analogues cured erythrocyticinfections after oral doses of 30 and 50 mg/kg × 4 days in a murine model while exhibiting good safety and metabolic profiles. This study presents the first account of multiple-stage antiplasmodial activities with rapid killing profile in the tambjamine family.