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. falciparum line. All compounds 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.

N¹,N¹-Dimethyl-N³-(3-(trifluoromethyl)phenethyl)propane-1,3-diamine, a new lead for the treatment of human African trypanosomiasis.

The natural product, convolutamine I (1), has anti-trypanosomal activity however it has a high molecular weight of 473 due to a presence of 3 bromine atoms. The synthesis of the natural product convolutamine I (1) together with its analogues are presented. A SAR study against Trypanosoma brucei brucei led to compounds with improved physico-chemical properties: lower molecular weight and lower log P while maintaining potency (with a slight 2-fold improvement).