Synthesis and In Vivo Profiling of Desymmetrized Antimalarial Trioxolanes with Diverse Carbamate Side Chains.

The recent withdrawal of artefenomel from clinical development leaves no endoperoxide-class agents in the antimalarial pipeline. Synthetic endoperoxides with a desymmetrized structure have demonstrated promising physiochemical and properties. Here we expand on our initial investigation of -3″ carbamate substitution with a diverse array of amine-, alcohol-, and sulfinyl-terminated analogues prepared in () and () configurations. In general, this chemotype combines low-nM antiplasmodial activity with excellent aqueous solubility but widely varying human liver microsome (HLM) stability. We evaluated 20 novel analogues in the mouse malaria model, identifying new analogues such as RLA-4767 () and RLA-5489 (), with HLM stability and pharmacokinetic profiles superior to analogues from our initial report (e.g., RLA-4776, ). These new leads approach or equal the efficacy of artefenomel after two daily oral doses of 10 mg/kg, thus revealing a promising chemotype with the potential to deliver development candidates.