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

Jun Yan; Jinhui Hu; Anqiu Liu; Lin He; Xingshu Li; Hui Wei

doi:10.1016/j.bmc.2017.02.048

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

Bioorg Med Chem. 2017 Jun 15;25(12):2946-2955. doi: 10.1016/j.bmc.2017.02.048. Epub 2017 Apr 18.

Authors

Jun Yan¹, Jinhui Hu¹, Anqiu Liu¹, Lin He², Xingshu Li¹, Hui Wei³

Affiliations

¹ School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
² School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan 528458, China; Guangdong Cosmetics Engineering & Technology Research Center, Zhongshan 528458, China.
³ School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan 528458, China; Guangdong Cosmetics Engineering & Technology Research Center, Zhongshan 528458, China. Electronic address: weihui75@sina.com.

PMID: 28454848
DOI: 10.1016/j.bmc.2017.02.048

Abstract

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=187nM) and the highest BuChE/AChE selectivity (66.3). Compound 11b also inhibited 45.3% Aβ_1-42 self-aggregation at 20μM and displayed remarkable antioxidant effects. The metal-chelating property of compound 11b 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.

Keywords: AChE inhibition; Alzheimer’s disease; Aβ(1–42) self-aggregation; Curcumin derivatives.

MeSH terms

Acetylcholinesterase / metabolism
Alzheimer Disease / drug therapy*
Alzheimer Disease / enzymology
Alzheimer Disease / metabolism
Amyloid beta-Peptides / metabolism*
Animals
Blood-Brain Barrier / metabolism
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / pharmacokinetics
Cholinesterase Inhibitors / pharmacology*
Curcumin / analogs & derivatives
Curcumin / pharmacokinetics
Curcumin / pharmacology*
Donepezil
Drug Design
Electrophorus
Humans
Indans / chemistry
Indans / pharmacokinetics
Indans / pharmacology*
Ligands
Molecular Docking Simulation
Molecular Targeted Therapy
Peptide Fragments / metabolism*
Piperidines / chemistry
Piperidines / pharmacokinetics
Piperidines / pharmacology*
Protein Aggregates / drug effects*
Swine

Substances

Amyloid beta-Peptides
Cholinesterase Inhibitors
Indans
Ligands
Peptide Fragments
Piperidines
Protein Aggregates
amyloid beta-protein (1-42)
Donepezil
Acetylcholinesterase
Curcumin