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

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

Abstract

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).

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

MeSH terms

  • Acetylcholinesterase / chemistry
  • Acetylcholinesterase / metabolism*
  • Amides / chemistry*
  • Amines / chemistry*
  • Butyrylcholinesterase / chemistry
  • Butyrylcholinesterase / metabolism*
  • Catalytic Domain
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / metabolism
  • Cholinesterase Inhibitors / pharmacology
  • Coumaric Acids / chemistry*
  • Coumaric Acids / metabolism
  • Coumaric Acids / pharmacology*
  • Kinetics
  • Molecular Docking Simulation
  • Structure-Activity Relationship

Substances

  • Amides
  • Amines
  • Cholinesterase Inhibitors
  • Coumaric Acids
  • ferulic acid
  • Acetylcholinesterase
  • Butyrylcholinesterase