Optimization of Tambjamines Active against Multiple Stages of Malaria Parasites.

Malaria remains a major global health challenge, demanding new therapies with novel mechanisms and multistage activity to overcome resistance. Previously, we developed a natural product-inspired novel antimalarial tambjamine chemotype that is potent against liver, asexual erythrocytic, and sexual erythrocytic parasite life cycle stages. Herein, we report a rigorous optimization strategy that expanded our chemical library and, more importantly, produced several lead tambjamines with excellent oral efficacy, while exhibiting feasible safety and metabolic profiles. Notably, KAR1123 (109) cured mice with erythrocytic Plasmodium yoelii infection after oral treatment of 25 mg/kg × 4 days or 80 mg/kg × 1 day and also provided partial protection against liver-stage Plasmodium berghei sporozoite-induced infection in mice. Profiling of compound 109 demonstrated a moderately fast in vitro parasite-killing profile. Furthermore, 109 displayed excellent potency against both artemisinin-resistant Plasmodium falciparum parasites and Ugandan P. falciparum clinical isolates.