Design and Synthesis of CNb-targeted Flavones and Analogues with Neuroprotective Potential Against H2O2- and Aβ1-42-Induced Toxicity in SH-SY5Y Human Neuroblastoma Cells

Ana Matos, Alice Martins, Teresa Man, David Evans, Magnus Walter, Maria Conceição Oliveira, Óscar López, José G. Fernandez-Bolaños, Philipp Dätwyler, Beat Ernst, M. Paula Macedo, Marialessandra Contino, Nicola A. Colabufo, Amélia P. Rauter

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With the lack of available drugs able to prevent the progression of Alzheimer’s disease (AD), the discovery of new neuroprotective treatments able to rescue neurons from cell injury is presently a matter of extreme importance and urgency. Here, we were inspired by the widely reported potential of natural flavonoids to build a library of novel flavones, chromen-4-ones and their C-glucosyl derivatives, and to explore their ability as neuroprotective agents with suitable pharmacokinetic profiles. All compounds were firstly evaluated in a parallel artificial membrane permeability assay (PAMPA) to assess their effective permeability across biological membranes, namely the blood-brain barrier (BBB). With this test, we aimed not only at assessing if our candidates would be well-distributed, but also at rationalizing the influence of the sugar moiety on the physicochemical properties. To complement our analvsis logD7.4 was determined. From all screened compounds, the p-morpholinyl flavones stood out for their ability to fully rescue SH-SY5Y human neuroblastoma cells against both H2O2 A β1-42-induced cell death. Cholinesterase inhibition was also evaluated, and modest inhibitory activities were found. This work highlights the potential of C-glucosylflavones as neuroprotective agents, and presents the p-morpholinyl C-glucosylflavone 37, which did not show any cytotoxicity towards HepG2 and Caco-2 cells at 100 ΜM, as a new lead structure for further development against AD.

Original languageEnglish
Article number98
Issue number2
Publication statusPublished - 1 Jun 2019


  • A β
  • Alzheimer’s disease
  • C-glucosyl flavonoids
  • Cholinesterase inhibitors
  • Chromen-4-ones
  • Flavones


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