Pd-Catalyzed Direct Modification Of An Anti-Alzheimer'S Disease Drug: Synthesis And Biological Evaluation Of Alpha-Aryl Donepezil Analogues

Palladium/BuAd(2)P efficiently catalyzed the direct alpha-arylation of ketone in the anti-Alzheimer's disease drug donepezil, leading to 15 aryldonepezil analogues exhibiting high selective inhibition of acetylcholinesterase (AChE). The cell-based assays revealed that the 3-methylpridinyl analogue (12) shows significantly lower toxicity compared to donepezil and remarkable neuroprotective activity against H2O2-induced damage in SH-SY5Y cells. Docking results of compound 12 also interpreted the possible mechanism of the selective inhibition between AChE and butyrylcholinesterase (BuChE).