PLASMEPSIN V INHIBITION AS A NEW POTENTIAL ANTIMALARIAL STRATEGY

Natural products have always played an important role in the drug discovery process. Plants, in particular, have formed the basis of a sophisticate traditional medicine system, and in many way they still provide inspiration and pharmacological inputs for the development of new active compounds. The history of malaria treatment is probably the best example of natural products importance in drug discovery: Quinine, the first therapeutic agent used against malaria, was isolated from the bark of Cinchona spp. in 1820, and its synthetic analogues were used until drug-resistance issues required new therapeutic agents to be developed. The answer to this problem was found in another plant, Artemisia annua, used in the treatment of fevers in Traditional Chinese Medicine (TCM). Artemisinin was extracted and characterized as a lead compound, and artemisinin analogues are now used for treatment of malaria in many countries, as part of artemisinin-combination therapies (ACTs). Unfortunately, after few years, an increasing number of Plasmodium falciparum strains started to develop resistance against these compounds. New therapeutic agents are needed to provide effective way to deal with resistant strain, and natural products could be used once again as a source of new chemical entities with antimalarial properties. While isolation and characterization of new natural products still play an important role in drug discovery, new strategies need to be investigated in order to speed up the process that lead from a natural extract with interesting pharmacological properties to a potential natural product lead compound in order to overcome chemistry and environmental issues. In this work, a new methodology to exploit natural products active compounds is presented. A common structure found in numerous natural products extracted from various biological sources is used as a starting point to create a small library to compounds that retain the biological activity of the starting product. The same strategy was then used to synthesize a new antimalarial compound combining a natural product scaffold with the information derived from an intensive SAR study on Plasmepsin V peptidomimetic inhibitors. This molecule, active against both chloroquine-resistant and choloroquine-sensitive P.f strains, may be used as a starting point for a new class of compound with potential PMV inhibition