Chromone derivatives bearing pyridinium moiety as multi-target-directed ligands against Alzheimer's disease.

Abstract

A new serise of 7-hydroxy-chromone derivatives bearing pyridine moiety were synthesized, and evaluated as multifunctional agents against Alzheimer's disease (AD). Most of the compounds were good AChE inhibitors (IC50 = 9.8-0.71 µM) and showed remarkable BuChE inhibition activity (IC50 = 1.9-0.006 µM) compared with donepezil as the standard drug (IC50 = 0.023 and 3.4 µM). Compounds 14 and 10 showed the best inhibitory activity toward AChE (IC50 = 0.71 µM) and BuChE (IC50 = 0.006 µM), respectively. The ligand-protein docking simulations and kinetic studies revealed that compound 14 and 10 could bind effectively to the peripheral anionic binding site (PAS) of the AChE and BuChE through mixed-type inhibition. In addition, the most potent compounds showed acceptable neuroprotective activity on H2O2- and Aβ-induced .neurotoxicity in PC12 cells, more than standard drugs. The compounds could block effectively self- and AChE-induced Aβ aggregation. All the results suggest that compounds 14 and 10 could be considered as promising multi-target-directed ligands against AD.

• Authors: Shahin Abdpour, Leili Jalili-Baleh, Hamid Nadri, Hamid Forootanfar, Syed Nasir Abbas Bukhari, Ali Ramazani, Seyed Esmaeil Sadat Ebrahimi, Alireza Foroumadi, Mehdi Khoobi
• Journal: Bioorganic chemistry (Bioorg Chem) Vol. 110 Pg. 104750 (05 2021) ISSN: 1090-2120 [Electronic] United States
• PMID: 33691251 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Cholinesterase Inhibitors
• Chromones
• Ligands
• Pyridinium Compounds
• Hydrogen Peroxide
• Acetylcholinesterase
• Butyrylcholinesterase

Topics

• Acetylcholinesterase (chemistry, metabolism)
• Alzheimer Disease (drug therapy)
• Animals
• Butyrylcholinesterase (chemistry, metabolism)
• Cell Survival (drug effects)
• Cholinesterase Inhibitors (chemical synthesis, pharmacology)
• Chromones (chemical synthesis, pharmacology)
• Dose-Response Relationship, Drug
• Drug Design
• Hydrogen Peroxide
• Ligands
• Models, Molecular
• Molecular Docking Simulation
• Molecular Structure
• PC12 Cells
• Pharmacokinetics
• Protein Conformation
• Pyridinium Compounds (chemistry, pharmacology)
• Rats