Synthesis and evaluation of donepezil-ferulic acid hybrids as multi-target-directed ligands against Alzheimer's disease

A novel family of donepezil-ferulic acid hybrids were designed, synthesized and biologically evaluated as multi-target-directed ligands against Alzheimer's disease by fusing a fragment of donepezil and ferulic acid. The in vitro assay indicated that some of these molecules exhibited potent cholinesterase inhibitory activities, outstanding radical scavenging activities and good neuroprotective effects on PC12 cells, and could penetrate into the central nervous system. Compound 5c especially showed moderate acetylcholinesterase inhibitory activity (IC50 values of 0.398 mu M for electric eel acetylcholinesterase) and butyrylcholinesterase inhibitory activity (IC50 = 0.976 mu M for equine serum butyrylcholinesterase). It also showed significant antioxidant activity (1.78 trolox equivalents by the ABTS method, IC50 values of 24.9 mu M by the DPPH method). The kinetic study and molecular docking indicated that compound 5c interacted with both the peripheral anionic site and the catalytic binding site of acetylcholinesterase. Overall, these results indicated that compound 5c is a promising drug candidate with balanced properties for the treatment of Alzheimer's disease.