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Développement de nouveaux agents antiparasitaires : vers la synthèse totale de la cissampeloflavone et de dérivés

Abstract : Tropical diseases caused by protozoan parasites such as Trypanosoma brucei, Plasmodium falciparum and Leishmania donovani, infect billions of people worldwide and kill millions of them every year. Nowadays, resistance phenomena against actual therapies used to treat these " neglected " diseases are becoming worring and problematic. Therefore, discovery of new classes of antiparasitic bioactive molecules is primordial.This is the aim of this PhD work. Cissampeloflavone is a chalcone-flavone dimer isolated in 2003 from a Venezuelan plant, Cissampelos pareira. This molecule has showed a good activity against Trypanosoma brucei (IC50 = 1 µM). Besides, molecular docking studies have predicted that its derivative 4-desoxycissampeloflavone would possess a good affinity for an essential enzyme for parasite survival. For these reasons, we undertook the total synthesis of these two original molecules never carried out to date.Simplified analogues have been prepared in order to elaborate a synthetic pathway to form cissampeloflavone and 4-desoxycissampeloflavone. These compounds possess the benzofuran ring as common core which bears either the "chalcone part" or the "flavone part" of these dimers. The total syntheses were then undertaken.This PhD work has particularly enabled the creation of a polysubstituted benzofuran library, the discovery of an original methylenation reaction and the formation of new furanoflavone derivatives. Most of them were evaluated on T. brucei, P. falciparum and L. donovani. Several compounds have showed an interesting and promising trypanocidal activity.
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Marion Thevenin. Développement de nouveaux agents antiparasitaires : vers la synthèse totale de la cissampeloflavone et de dérivés. Autre. Université Paris Sud - Paris XI, 2013. Français. ⟨NNT : 2013PA112173⟩. ⟨tel-00871981⟩

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