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 <i>in vivo</i> properties. Here we expand on our initial investigation of <i>trans</i>-3″ carbamate substitution with a diverse array of amine-, alcohol-, and sulfinyl-terminated analogues prepared in (<i>S,S</i>) and (<i>R,R</i>) 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 <i>P. berghei</i> mouse malaria model, identifying new analogues such as RLA-4767 (<b>9a</b>) and RLA-5489 (<b>9d</b>), with HLM stability and pharmacokinetic profiles superior to analogues from our initial report (e.g., RLA-4776, <b>8a</b>). 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.