Simple analogues of natural product chelerythrine: Discovery of a novel anticholinesterase 2-phenylisoquinolin-2-ium scaffold with excellent potency against acetylcholinesterase

Eur J Med Chem. 2020 Aug 15:200:112415. doi: 10.1016/j.ejmech.2020.112415. Epub 2020 May 16.


As simple analogues of the natural compound chelerythrine, a novel anti-cholinesterase 2-phenylisoquinolin-2-ium scaffold was designed by structure imitation. The activity evaluation led to the discovery of seven compounds with potent anti-acetylcholinesterase activity with IC50 values of ≤0.72 μM, superior to chelerythrine and standard drugs galantamine. Particularly, compound 8y showed the excellent dual acetylcholinesterase-butyrylcholinesterase inhibition activity, superior to rivastigmine, a dual cholinesterase inhibitor drug. Furthermore, the compounds displayed a competitive anti-acetylcholinesterase mechanism with the substrate and low cytotoxicity. Molecular docking showed that the isoquinoline moiety is embedded in a cavity surrounded by four aromatic residues of acetylcholinesterase by the π-π action. Structure-activity relationship showed that the p-substituents on the C-ring can dramatically improve the anti-acetylcholinesterase activity, while 8-OMe can increase the activity against the two cholinesterases simultaneously. Thus, the title compounds emerged as promising lead compounds for the development of novel cholinesterase inhibitor agents.

Keywords: Acetylcholinesterase; Benzo[c]phenanthridine; Butyrylcholinesterase; Isoquinoline; Molecular docking; Structure-activity relationship.

MeSH terms

  • Benzophenanthridines / chemistry*
  • Binding Sites
  • Butyrylcholinesterase
  • Cholinesterase Inhibitors / chemistry*
  • Cholinesterase Inhibitors / metabolism
  • Drug Discovery*
  • Humans
  • Inhibitory Concentration 50
  • Isoquinolines / chemistry
  • Isoquinolines / pharmacology
  • Molecular Docking Simulation
  • Structure-Activity Relationship


  • Benzophenanthridines
  • Cholinesterase Inhibitors
  • Isoquinolines
  • chelerythrine
  • Butyrylcholinesterase
  • isoquinoline