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Pharmacochimie des aurones pour la modulation d'enzymes

Abstract : Aurones, a subclass of flavonoids, present a favorable pharmacological profile and a wide, promising spectrum of biological activites. During this work, we used this potential for the modulation of two major therapeutic targets. Firstly, since several hepatitis C virus protease NS3/4A inhibitors were recently marketed, the inhibition of the polymerase NS5B is now the focus of research efforts in the fight against HCV. The use of aurones against the HCV polymerase is here reported for the first time. Four generations of compounds were synthesized and evaluated, and several bioactive derivatives were found, including some natural products, with an IC50 below 5 μM. Furthermore, additional investigations regarding inhibitor – receptor interactions allowed to identify the aurones binding site, which is Thumb Site I. Secondly, although the modulation of tyrosinase in a therapeutic aim remains a matter of discussion, a number of studies considers this enzyme as a potential target for future treatments against some hardly curable diseases, such as cancer or Parkinson's disease. During this work, aurones showed a great versatility toward tyrosinase. According to their substitution pattern, the compounds embraced very different behaviours, i.e. alternative substrate, hyperbolic activator or mixed inhibitor behaviour. However a consistent model was proposed, which gathers and explains all of these behaviours. During this study, a large number of widely substituted or modified aurone derivatives were prepared, according to structure-dependant adaptative synthetic methods.
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Submitted on : Friday, May 31, 2013 - 1:02:35 AM
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  • HAL Id : tel-00828395, version 1



Romain Haudecoeur. Pharmacochimie des aurones pour la modulation d'enzymes. Autre. Université de Grenoble; Université de Genève. Faculté des sciences, 2011. Français. ⟨NNT : 2011GRENV063⟩. ⟨tel-00828395⟩



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