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.