Total synthesis of thiaplakortone a: derivatives as metabolically stable leads for the treatment of malaria.

Thiaplakortone A (3a), an antimalarial natural product, was prepared by an operationally simple and scalable synthesis. In our efforts to deliver a lead compound with improved potency, metabolic stability, and selectivity, the synthesis was diverted to access a series of analogues. Compounds 3a-d showed nanomolar activity against the chloroquine-sensitive (3D7) Plasmodium falciparum line and were more active against the chloroquine- and mefloquine-resistant (Dd2) P.