Synthesis, biological assessment and molecular modeling of 14-aryl-10,11,12,14-tetrahydro-9H-benzo[5,6]chromeno[2,3-b]quinolin-13-amines

Emna Maalej, Fakher Chabchoub, Abdelouahid Samadi, Cristóbal De Los Ríos, Almudena Perona, Antonio Morreale, José Marco-Contelles

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)

Abstract

The synthesis and pharmacological evaluation of racemic 14-aryl-10,11,12,14-tetrahydro-9H-benzo[5,6]chromeno[2,3-b]quinolin-13-amines (19-28), prepared by Friedländer reaction of 3-amino-1-aryl-1H-benzo[f] chromene-2-carbonitriles (10-18) with suitable cycloalkanones is described. These molecules are potent, in the nanomolar range [IC50 (EeAChE) = 7-101 nM], and selective inhibitors of acetylcholinesterase (AChE). The most potent inhibitor, 4-(13-amino-10,11,12,14-tetrahydro-9H-benzo[5,6]chromeno[2,3- b]quinolin-14-yl)phenol (20) [IC50 (EeAChE) = 7 ± 2 nM] is four-fold more active than tacrine. Kinetic studies on compound 20 showed that this is a mixed-type inhibitor of EeAChE with a Ki of 5.00 nM. However, racemic 20 was unable to displace propidium iodide, suggesting that the inhibitor does not strongly bind to the peripheral anionic site (PAS) of AChE. Docking, molecular dynamics stimulations, and MM-GBSA calculations agree well with this behavior.

Original languageEnglish
Pages (from-to)2384-2388
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume21
Issue number8
DOIs
Publication statusPublished - Apr 15 2011
Externally publishedYes

Keywords

  • AChE
  • Alzheimer's disease
  • BuChE
  • Docking analysis
  • Inhibition mechanism
  • Kinetic analysis
  • Molecular dynamics simulation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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