Design, synthesis, and evaluation of chalcone-Vitamin E-donepezil hybrids as multi-target-directed ligands for the treatment of Alzheimer's disease.

A novel series of chalcone-Vitamin E-donepezil hybrids was designed and developed based on multitarget-directed ligands (MTDLs) strategy for treating Alzheimer's disease (AD). The biological results revealed that compound showed good AChE inhibitory potency (AChE IC = 0.41 µM; AChE IC = 1.88 µM). Both the kinetic analysis and docking study revealed that was a mixed type AChE inhibitor. was also a good antioxidant (ORAC = 3.3 ), selective metal chelator and MAO-B inhibitor (IC = 8.8 µM). Moreover, it showed remarkable inhibition of self- and Cu-induced A aggregation with a 78.0 and 93.5% percentage rate at 25 µM, respectively, and disassembled self-induced and Cu-induced aggregation of the accumulated A fibrils with 72.3 and 84.5% disaggregation rate, respectively. More importantly, exhibited a good neuroprotective effect on HO-induced PC12 cell injury and presented good blood-brain barrier permeability . Thus, was a promising multi-target-directed ligand for treating AD.