Affiliations 

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla, Thailand
  • 2 Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Songkhla, Thailand
  • 3 Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla, Thailand
  • 4 Faculty of Medicine, Institute of Biomedical Engineering, Prince of Songkla University, Songkhla, Thailand
  • 5 Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia
  • 6 Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur, Malaysia
Arch Pharm (Weinheim), 2019 Jul;352(7):e1800310.
PMID: 31125474 DOI: 10.1002/ardp.201800310

Abstract

Sixteen novel coumarin-based compounds are reported as potent acetylcholinesterase (AChE) inhibitors. The most active compound in this series, 5a (IC50 0.04 ± 0.01 µM), noncompetitively inhibited AChE with a higher potency than tacrine and galantamine. Compounds 5d, 5j, and 5 m showed a moderate antilipid peroxidation activity. The compounds showed cytotoxicity in the same range as the standard drugs in HEK-293 cells. Molecular docking demonstrated that 5a acted as a dual binding site inhibitor. The coumarin moiety occupied the peripheral anionic site and showed π-π interaction with Trp278. The tertiary amino group displayed significant cation-π interaction with Phe329. The aromatic group showed π-π interaction with Trp83 at the catalytic anionic site. The long chain of methylene lay along the gorge interacting with Phe330 via hydrophobic interaction. Molecular docking was applied to postulate the selectivity toward AChE of 5a in comparison with donepezil and tacrine. Structural insights into the selectivity of the coumarin derivatives toward huAChE were explored by molecular docking and 3D QSAR and molecular dynamics simulation for 20 ns. ADMET analysis suggested that the 2-(2-oxo-2H-chromen-4-yl)acetamides showed a good pharmacokinetic profile and no hepatotoxicity. These coumarin derivatives showed high potential for further development as anti-Alzheimer agents.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.