In 2010, approximately 655,000 people died from malaria. Of these deaths, an estimated 91 percent occurred in sub-Saharan Africa, predominantly affecting children under the age of five. Approximately 3.3 billion people, almost half the world’s population, including the populations of Africa, Asia, Latin America, the Middle East and South East Asia, are at risk of developing malaria.1 Frontline defences against malaria are under threat due to parasite drug resistance to all currently available antimalarial drugs. New antimalarial drugs with unique mechanisms are urgently needed in order to combat the global problem of parasite drug resistance.
In an effort to identify potential antimalarial lead- or drug-like natural products following high-throughput screening (HTS) campaigns, we have recently screened a pre-fractionated natural product library. Several antiplasmodial natural products, from a variety of different structure classes and biota sources, were identified during this research. The potent and selective antiplasmodial natural product thiaplakortone A was prepared by an efficient and scalable total synthesis. Diversion of the total synthesis generated a series of analogues, yielding comparably active compounds with improved metabolic stability. This work paves the way for the development of structurally unprecedented lead compounds for the treatment of malaria.