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Eur J Med Chem. 2017 Jan 27;126:810-822. doi: 10.1016/j.ejmech.2016.12.003. Epub 2016 Dec 2.

Novel ferulic amide derivatives with tertiary amine side chain as acetylcholinesterase and butyrylcholinesterase inhibitors: The influence of carbon spacer length, alkylamine and aromatic group.

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College of Chemistry and Chemical Engineering, Hu'nan University, Changsha 410082, China.
College of Pharmacy, Hu'nan University of Chinese Medicine, Changsha 410208, China.
College of Medicine, Hu'nan Normal University, Changsha 410013, China. Electronic address:
College of Medicine, Hu'nan Normal University, Changsha 410013, China.


Based on our recent investigations on chalcone derivatives as AChE inhibitors, a series of ferulic acid (FA) tertiary amine derivatives similar to chalcone compounds were designed and synthesized. The results of bioactivity evaluation revealed that most of new synthesized compounds had comparable or more potent AChE inhibitory activity than the control drug Rivastigmine. The alteration of carbon chain linking tertiary amine groups and ferulic acid scaffold markedly influenced the inhibition activity against AChE. Among them the inhibitory activity of compound 6d (IC50: 0.71 ± 0.09 μmol/L) and 6e (IC50: 1.11 ± 0.17 μmol/L) was equal to 15-fold and 9-fold than that of Rivastigmine against AChE (IC50: 10.54 ± 0.86 μmol/L), respectively. Moreover, compound 6d shows the highest selectivity for AChE over butyrylcholinesterase(BuChE) (ratio: 18.3). The kinetic study suggested that compound 6d revealed a mixed-type inhibition against AChE. The result of molecular docking showed that compound 6d combines to AChE with three amino acid sites(Trp84, Tyr334 and Trp279), while combines to BuChE with two amino acid sites (Tyr67 and Gly66) in enzyme domains, respectively. Compound 6d might act as a potential agent for the treatment of Alzheimer's diseases (AD).


Acetylcholinesterases; Alzheimer's disease; Ferulic acid; Molecular docking; α,β-Unsaturated carbonyl

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