Galantamine-Curcumin Hybrids as Dual-Site Binding Acetylcholinesterase Inhibitors

Molecules. 2020 Jul 23;25(15):3341. doi: 10.3390/molecules25153341.

Abstract

Galantamine (GAL) and curcumin (CU) are alkaloids used to improve symptomatically neurodegenerative conditions like Alzheimer's disease (AD). GAL acts mainly as an inhibitor of the enzyme acetylcholinesterase (AChE). CU binds to amyloid-beta (Aβ) oligomers and inhibits the formation of Aβ plaques. Here, we combine GAL core with CU fragments and design a combinatorial library of GAL-CU hybrids as dual-site binding AChE inhibitors. The designed hybrids are screened for optimal ADME properties and BBB permeability and docked on AChE. The 14 best performing compounds are synthesized and tested in vitro for neurotoxicity and anti-AChE activity. Five of them are less toxic than GAL and CU and show activities between 41 and 186 times higher than GAL.

Keywords: ADME; BBB permeability; molecular docking; neurotoxicity; virtual screening.

MeSH terms

  • Acetylcholinesterase / chemistry
  • Acetylcholinesterase / metabolism*
  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / metabolism*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Binding Sites
  • Blood-Brain Barrier / metabolism
  • Cell Line
  • Cholinesterase Inhibitors / chemical synthesis*
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology
  • Combinatorial Chemistry Techniques
  • Curcumin / chemistry*
  • Galantamine / chemical synthesis*
  • Galantamine / chemistry
  • Galantamine / pharmacology
  • Humans
  • Mice
  • Molecular Docking Simulation
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Amyloid beta-Peptides
  • Cholinesterase Inhibitors
  • Galantamine
  • Acetylcholinesterase
  • Curcumin