%0 Journal Article
%T Design and Synthesis of CNS-targeted Flavones and Analogues with Neuroprotective Potential Against H2O2- and A¦Â1-42-Induced Toxicity in SH-SY5Y Human Neuroblastoma Cells
%J Pharmaceuticals | An Open Access Journal from MDPI
%D 2019
%R https://doi.org/10.3390/ph12020098
%X 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 analysis, log D 7.4 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 H 2O 2- and A¦Â 1-42-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 ¦ÌM, as a new lead structure for further development against AD. View Full-Tex
%U https://www.mdpi.com/1424-8247/12/2/98