Prodrugs oF antiparasitic RedOx-active compoundS

With 600,000 deaths per year, malaria remains the most devastating parasitic disease for humans. The efficiency of artemisinin-based combination therapy, the spearhead of malarial treatment, is now threatened by the development of drug resistant parasites displaying enhanced transmission potential to mosquitoes. Chagas disease, leishmaniasis and schistosomiasis are neglected tropical parasitic diseases that are considered as the greatest missed opportunities atop the priorities for WHO. The FeROS project is based on the discovery of promising non-quinonoid chemotypes as precursors of 3-benzylmenadiones, with specific antiparasitic profiles depending on the substitution pattern. FeROS will follow convergent and complementary objectives: (i) to develop innovative and specific antiparasitic prodrugs in specific series of optimized drug-candidates to reach total cures in infected animal models for four human parasitic diseases, (ii) to extend the concept to animal health, (iii) to draw structure-activity relationships in in vitro and in vivo parasite assays, (iv) to build innovative chemical tools to visualize the release of active principles under ROS fluxes, in living parasites upon drug treatment, (v) to decipher the molecular and cellular mechanisms that underlie prodrug antiparasitic activities and selectivity. FeROS is built on the multidisciplinary expertise of 7 laboratories from France, Belgium, Switzerland and USA. In an interdisciplinary approach, we will combine a large set of expertise, ranging from medicinal chemistry, physico(bio)chemistry, proteomics to parasite genetics and molecular and cellular parasitology to optimize the antiparasitic non-quinonoid prodrugs of 3-benzylmenadiones, to unravel their mode of action and take them to early clinical studies.