Synthesis\nand In Vivo Profiling of Desymmetrized Antimalarial\nTrioxolanes with Diverse Carbamate Side Chains

The recent withdrawal of artefenomel from clinical development\nleaves no endoperoxide-class agents in the antimalarial pipeline.\nSynthetic endoperoxides with a desymmetrized structure have demonstrated\npromising physiochemical and <i>in vivo</i> properties.\nHere we expand on our initial investigation of <i>trans</i>-3″ carbamate substitution with a diverse array of amine-,\nalcohol-, and sulfinyl-terminated analogues prepared in (<i>S,S</i>) and (<i>R,R</i>) configurations. In general, this chemotype\ncombines low-nM antiplasmodial activity with excellent aqueous solubility\nbut widely varying human liver microsome (HLM) stability. We evaluated\n20 novel analogues in the <i>P. berghei</i> mouse malaria\nmodel, identifying new analogues such as RLA-4767 (<b>9a</b>) and RLA-5489 (<b>9d</b>), with HLM stability and pharmacokinetic\nprofiles superior to analogues from our initial report (e.g., RLA-4776, <b>8a</b>). These new leads approach or equal the efficacy of artefenomel\nafter two daily oral doses of 10 mg/kg, thus revealing a promising\nchemotype with the potential to deliver development candidates.