Semi-synthetic isoflavones as BACE-1 inhibitors against Alzheimer's disease.

• Twelve semi-synthetic derivatives of prenylated isoflavones 5 - 16 were designed and synthesized. • Derivatives were evaluated via human recombinant BACE-1 inhibition and cytotoxicity assay. • 7 , 8 and 13 were found to be the most active candidates. • These compounds were targeted for the BACE-1 enzyme and P-glycoprotein (P-gp) in docking studies. • 7 enhance the activity of P-glycoprotein (P-gp) on A549 cancer cells. BACE-1 is considered to be one of the targets for prevention and treatment of Alzheimer's disease (AD). We here report a novel class of semi-synthetic derivatives of prenylated isoflavones, obtained from the derivatization of natural flavonoids from Maclura pomifera. In vitro anti-AD effect of the synthesized compounds were evaluated via human recombinant BACE-1 inhibition assay. Compound 7 , 8 and 13 were found to be the most active candidates which demonstrates good correlation between the computational docking and pharmacokinetic predictions. Moreover, cytotoxic studies demonstrated that the compounds are not toxic against normal and cancer cell lines. Among these three compounds, compound 7 enhance the activity of P-glycoprotein (P-gp) on A549 cancer cells and increases the activity of P-gp ATPase with a possible role on the efflux of amyloid-β across the blood- brain barrier. In conclusion, the present findings may pave the way for the discovery of a novel class of compounds to prevent and/or treat AD. [ABSTRACT FROM AUTHOR]