Recherche des molécules antiparasitaires à l’interface de l’ethnopharmacologie, des sciences analytiques et de la biologie

Abstract : This work is developed in 3 chapters. The first chapter describes an ethopharmacological work in two Mestizos communities from Peruvian Amazonia. Results include an inventory of 46 plants grouped according to their uses and traditional preparations. In vitro activities on three parasites (Plasmodium falciparum, Leishmania donovani, Trypanosoma brucei gambiense) and their cytotoxicity are reported. Among all these plants Grias neuberthii (Lecythidaceae) and Costus curvibracteatus (Costaceae) showed a strong antiparasitic activity, associated with a strong cytotoxicity for C. curvibracteatus.The second chapter describes the exploration by mass spectrometry (MS) in a biomimetic environment mimicking the digestive vacuole of Plasmodium (DVP), the intermolecular bond between heme and ligands. Results for methoxyflavones suggested that there is no positive relation between the stability of the heme adduct and the biological activity on two P. falciparum strains (3D7 and W2). A correlation was suggested between the presence of a methoxy substitution in R5 of the flavone, heme binding and hydrophobicity (cLogP). This relation could be partially explained by the influence of the carbonyl group on hydrogen bounding. Docking analyses were performed to understand the electrostatic forces involved in the binding. The same kind of study was applied on original fluorescent probes based on artemisinin skeleton (ART). Stability of the heme adduct with the probes, evaluated by CID, showed similarities with ART. Stability of three probes in different conditions mimicking Plasmodium biology were evaluated.The third chapter presents the development of a crude extract biodereplication method, using heme-binding methodology by MS. The plant Piper coruscans (Piperaceae) was selected for this application. MSMS adducts visualization was performed by molecular networking. Targeted products were isolated by centrifugal partition chromatography or preparative liquid chromatography, in one or two steps. Thirteen molecules were isolated, including ten already known products: six flavanones, three chalcones, one alkylamide, one indanone isolated for the first time like a natural product and two new coumpounds: one kavalactone and one cinnamic acid derivative. Among all these molecules, a chalcone validated the biological activity of the plant and showed an intermolecular bound with heme.
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Pedro Vasquez Ocmin. Recherche des molécules antiparasitaires à l’interface de l’ethnopharmacologie, des sciences analytiques et de la biologie. Chimie thérapeutique. Université Paris-Saclay, 2018. Français. ⟨NNT : 2018SACLS479⟩. ⟨tel-02153075⟩

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