Exploring the structure-activity relationship of benzylidene-2,3-dihydro-1H-inden-1-one compared to benzofuran-3(2H)-one derivatives as inhibitors of tau amyloid fibers - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue European Journal of Medicinal Chemistry Année : 2022

Exploring the structure-activity relationship of benzylidene-2,3-dihydro-1H-inden-1-one compared to benzofuran-3(2H)-one derivatives as inhibitors of tau amyloid fibers

Antoine Fortuné
Marine Peuchmaur

Résumé

Tauopathies, such as Alzheimer's disease, have been the subject of several hypotheses regarding the way to treat them. Hyperphosphorylation of tau protein leading to its aggregation is widely recognized as a key step in the development of these diseases resulting in neuronal dysfunction. The AcPHF6 model of tau that includes the shorter critical fragment involved in the protein aggregation was used in vitro to identify new potential inhibitors. Following a previous study on aurone derivatives, we herein compare this polyphenol family to a very close one, the benzylidene-2,3-dihydro-1H-inden-1-one (also named indanone). The structure activity relationship studies bring to light the importance of the hydroxylation pattern in both series: the more hydroxylated, the more active. In addition, the three-dimensional shape of the molecules is involved in the way they interact with their target, thus defining either a role as an inhibitor of fiber elongation or as a chemical probe of fibers. Compound 13a was identified as a promising inhibitor: its activity was confirmed by circular dichroism and atomic force microscopy studies.
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hal-04014492 , version 1 (04-03-2023)

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Emeline Boukherrouba, Camille Larosa, Kim-Anh Nguyen, Jérémy Caburet, Laurent Lunven, et al.. Exploring the structure-activity relationship of benzylidene-2,3-dihydro-1H-inden-1-one compared to benzofuran-3(2H)-one derivatives as inhibitors of tau amyloid fibers. European Journal of Medicinal Chemistry, 2022, 231, pp.114139. ⟨10.1016/j.ejmech.2022.114139⟩. ⟨hal-04014492⟩
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