New potent antimalarial agents through natural products assembly

About 40% of the world’s population lives with risks to contract malaria, with estimates of 800,000 deaths per year. Although expanded control programs are under way as to inhibit infection transmission, treating ill patients, including children and pregnant women, still appears of limited solution, mainly due to drug resistance and Plasmodium recrudescence. One of the most promising concept is to study small molecules as transmission blocking agents and to exploit targets alternative to those that are known to be involved in resistance. Our strategy relies on the study of natural products accessible from Nature in high yields or available through economic synthetic approaches. Previous knowledge indicated that some natural acylphloroglucinols possess a putative antiplasmodial activity, both acting at erythrocytic and exoerythrocytic stages. (+)-Usnic acid, a compound widely spread in lichens, was tested against different stages of malaria parasite life cycle, observing a good activity in vitro; the absence of activity in vivo is probably due to its rapid clearance. On the basis of these results this scaffold was derivatised in order to obtain compounds with improved antiprotozoal properties. Conjugates of known antimalarial aminoquinolines and endoperoxides were prepared, resulting in remarkably active compounds.