Aminium Radicals for Discovering Novel Antiparasite Endoperoxides (ARDIROX)

Endoperoxides constitute an emerging but under-explored class of agents against leishmaniases, which are neglected diseases of human and veterinary importance. In the case of malaria, their remarkable and still unparalleled efficacy has already been established, even though the best treatments currently in use are threatened by resistance phenomena. Thanks to the expertise of the molecular chemists of the consortium (LSO laboratory, UMR 7652 CNRS/École Polytechnique and UMR PASTEUR-8640, CNRS/ENS Paris), ARDIROX will address the challenge of exploring a fully original synthetic route to novel endoperoxides, by taking advantage of the chemistry of aminium radicals. The target molecules will be prepared in a controlled and environmentally-friendly fashion, without the use of any expensive or toxic catalyst. Two types of simple precursors having diverse structures will be studied. Electrochemistry will play a key role in these investigations, in line with this sustainable development perspective: cyclic voltammetry will provide valuable information on the redox properties of the substrates and endoperoxides will be prepared by electrosynthesis. A supplementary added-value will consist in combining, within some single molecules, an endoperoxide and a scaffold already known to exhibit antiparasitic activities, in order to trigger different mechanisms of action, opening the possibility of a synergistic effect and/or a reduction of the risk of drug resistance. In close cooperation with their biologist partners (UMR 8076 CNRS/BioCIS Paris-Saclay and UMR 7245, CNRS/MNHN Paris), the chemists will progressively improve the targeted molecules of interest, according to their measured effect on the parasites. The assays will be carried out in depth on Leishmania donovani, which is responsible for visceral leishmaniasis, as well as on Leishmania major, which causes cutaneous leishmaniasis. The biological studies will systematically include an evaluation of activity against Plasmodium. In addition to the discovery of new active molecules, this work will help disclosing possible similarities of the mechanisms of action of endoperoxides, depending on the genus of pathogenic parasites, Leishmania or Plasmodium.

Project details

Product Development

Jan 2023 — Jan 2027

$535,198

France