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Modifications fonctionnelles en position C2 des 8-alkylthiazolo[5,4-f]quinazolin-9(8H)-ones et stratégie d’extension de fragment pour la synthèse d’inhibiteurs de kinases de la famille DYRK

Abstract : The effects of expression modulation of protein kinases DYRK (Dual-specificity tyrosine phosphorylation-regulated kinase) and especially of DYRK1A are characterized in a variety of diseases including neurodegenerative diseases (Alzheimer’s disease or Down syndrome) and cancers. This thesis deals with our laboratory knowledge and previous results obtained with thiazolo[5,4-f]quinazolines and thiazolo[5,4-f]quinazolin-9(8H)-ones and their activity. The main part of this thesis is focused on the C2-modulation of thiazolo[5,4-f]quinazolin-9(8H)-ones to synthesize potent DYRK1A inhibitors. The first chapter of this manuscript describes the addition of nucleophiles such as amino acids at the C2-function of 8-benzylthiazolo[5,4-f]quinazolin-9(8H)-ones. The second chapter is focused on the optimization of the thiazolo[5,4-f]quinazolin-9(8H)-ones synthesis and their C–H arylation. Deprotection of C2-arylated products and C–H alkenylation approach of 8-benzylthiazolo[5,4-f]quinazolin-9(8H)-one are also described. The third chapter deals with the inhibitory activity evaluation of most of the compounds prepared along this work shown FC162 as DYRK1A inhibitor. These results led to C2 modulation of simpler structures such as benzo[d]thiazoles by studying the C–H arylation of these bicyclic derivatives.
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Florence Couly. Modifications fonctionnelles en position C2 des 8-alkylthiazolo[5,4-f]quinazolin-9(8H)-ones et stratégie d’extension de fragment pour la synthèse d’inhibiteurs de kinases de la famille DYRK. Chimie organique. Normandie Université, 2018. Français. ⟨NNT : 2018NORMIR12⟩. ⟨tel-01997231⟩

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