Inhibition of cholinesterase activity and amyloid aggregation by berberine-phenyl-benzoheterocyclic and tacrine-phenyl-benzoheterocyclic hybrids

Bioorg Med Chem. 2012 May 1;20(9):3038-48. doi: 10.1016/j.bmc.2012.02.059. Epub 2012 Mar 10.

Abstract

A series of berberine-phenyl-benzoheterocyclic (26-29) and tacrine-phenyl-benzoheterocyclic hybrids (44-46) were synthesised and evaluated as multifunctional anti-Alzheimer's disease agents. Compound 44b, tacrine linked with phenyl-benzothiazole by 3-carbon spacers, was the most potent AChE inhibitor with an IC(50) value of 0.017 μM. This compound demonstrated similar Aβ aggregation inhibitory activity with cucurmin (51.8% vs 52.1% at 20 μM, respectively), indicating that this hybrid is an excellent multifunctional drug candidate for AD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism
  • Alzheimer Disease / drug therapy
  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Amyloid beta-Peptides / metabolism
  • Berberine / chemistry*
  • Binding Sites
  • Butyrylcholinesterase / metabolism
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry*
  • Cholinesterase Inhibitors / pharmacology*
  • Cholinesterases / chemistry
  • Cholinesterases / metabolism*
  • Enzyme Activation / drug effects
  • Heterocyclic Compounds / chemistry*
  • Heterocyclic Compounds / pharmacology
  • Humans
  • Kinetics
  • Molecular Dynamics Simulation
  • Protein Structure, Tertiary
  • Tacrine / chemistry*

Substances

  • Amyloid beta-Peptides
  • Cholinesterase Inhibitors
  • Heterocyclic Compounds
  • Berberine
  • Tacrine
  • Acetylcholinesterase
  • Butyrylcholinesterase
  • Cholinesterases