Design, synthesis, and evaluation of multitarget-directed ligands against Alzheimer's disease based on the fusion of donepezil and curcumin

By fusing donepezil and curcumin, a novel series of compounds were obtained as multitarget-directed ligands against Alzheimer's disease. Among them, compound 11b displayed potent acetylcholinesterase (AChE) inhibition (IC50 = 187 nM) and the highest BuChE/AChE selectivity (66.3). Compound lib also inhibited 45.3% A beta(1-42) self-aggregation at 20 mu M and displayed remarkable antioxidant effects. The metal-chelating property of compound lib was elucidated by determining the 1:1 stoichiometry for the 11b-Cu(II) complex. The excellent blood-brain barrier permeability of 11b also indicated the potential for the compound to penetrate the central nervous system. (C) 2017 Elsevier Ltd. All rights reserved.