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Etude des interactions molécules d'intérêt pharmacologique/modèles membranaires : cas des polyènes et de nouvelles molécules antipaludiques

Abstract : The main purpose of this work is to better understand the mechanisms of interaction between pharmaceutical relevant molecules and model membranes in order to facilitate the synthesis of new molecules, more efficient against their molecular target and less toxic for Humans. In the first part, we studied the interactions occuring between these models and antifungal polyene molecules. It has been reported that these molecules interacted preferentially with sterols. We specifically focused on Nystatin and Amphotericin B, two polyenes with a very similar chemical structure and presently used as a treatment against fungi and molds. Using different kind of model membranes, we showed PhosphatidylEthanolamine could have a very important role in the mechanism of action of these molecules. In the second part of this work, we studied the inhibition of the formation of a cristal called « hemozoïn », which is growing during the life cycle of the parasite responsible of malaria. This cristal is made of hematin, a toxic by-product of the degradation of hemoglobin, the main source of amino-acids for the parasite. Hematin and the inhibition of the growth of this cristal is a ideal molecular target to combat malaria. Chloroquine, mefloquine and new mefloquine-derivatives were studied. The study of the inhibition of the formation of the cristal was done using Langmuir monolayers as a biosensor. We showed that stereochemistry, but also lipophilicity of these compounds, are important parameters for the synthesis of more efficient antimalarial molecules.
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Thierry-Johann Robin. Etude des interactions molécules d'intérêt pharmacologique/modèles membranaires : cas des polyènes et de nouvelles molécules antipaludiques. Biotechnologies. Université de Technologie de Compiègne, 2014. Français. ⟨NNT : 2014COMP2165⟩. ⟨tel-01228513⟩

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