Thiaplakortone A (I), an antimalarial natural product, was prepd. by an operationally simple and scalable synthesis. In our efforts to deliver a lead compd. with improved potency, metabolic stability, and selectivity, the synthesis was diverted to access a series of analogs. Several compds. showed nanomolar activity against the chloroquine-sensitive (3D7) Plasmodium falciparum line and were more active against the chloroquine- and mefloquine-resistant (Dd2) P. falciparum line. All compds. are “Rule-of-5” compliant, and we show that metabolic stability can be enhanced via modification at either the primary or pyrrole nitrogen. These promising results lay the foundation for the development of this structurally unprecedented natural product.