Amine substitution of quinazolinones leads to selective nanomolar AChE inhibitors with 'inverted' binding mode

Bioorg Med Chem. 2014 Sep 1;22(17):4867-81. doi: 10.1016/j.bmc.2014.06.045. Epub 2014 Jul 1.


Selective and nanomolar acetylcholinesterase inhibitors were obtained by connecting tri- and tetracyclic quinazolinones-previously described as moderately active and unselective cholinesterase (ChE) inhibitors-via a hydroxyl group in para position to an anilinic nitrogen with different amines linked via a three carbon atom spacer. These tri- and tetracyclic quinazolinones containing different alicyclic ring sizes and connected to tertiary amines were docked to a high-resolution hAChE crystal structure to investigate the preferred binding mode in relation to results obtained by experimental structure-activity relationships. While the 'classical orientation' locating the heterocycle in the active site was rarely found, an alternative binding mode with the basic aliphatic amine in the active center ('inverted' orientation) was obtained for most compounds. Analyses of extended SARs based on this inverted binding mode are able to explain the compounds' binding affinities at AChE.

Keywords: Alzheimer’s disease; Cholinesterase inhibitors; Computational study; Heterocycles; Quinazolinones.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism*
  • Amines / chemistry*
  • Binding Sites / drug effects
  • Butyrylcholinesterase / metabolism*
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Quinazolinones / chemical synthesis
  • Quinazolinones / chemistry
  • Quinazolinones / pharmacology*
  • Structure-Activity Relationship


  • Amines
  • Cholinesterase Inhibitors
  • Quinazolinones
  • Acetylcholinesterase
  • Butyrylcholinesterase