Total Synthesis of Thiaplakortone A: Derivatives as Metabolically Stable Leads for the Treatment of Malaria

• DOI: 10.1021/ml400447v
• Publication Date: 2013-12-27T15:48:09Z
• Authors: Rebecca H. Pouwer; Sophie M. Deydier; Phuc Van Le; Brett D. Schwartz; Nicole C. Franken; Rohan A. Davis; Mark J. Coster; Susan A. Charman; Michael D. Edstein; Tina S. Skinner-A...; Katherine T. Andrews; Ian D. Jenkins; Ronald J. Quinn
• Keywords: Pharmacology and pharmaceutical sciences; Medicinal and biomolecular chemistry; Organic chemistry; 540; 01 natural sciences; Medicinal and biomolecular chemistry not elsewhere classified; 0104 chemical sciences; 3. Good health

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