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Cholinesterase Inhibition Activity and Docking Simulation Study of Coumarin Mannich Base Derivatives



Kiani A1 ; Jalilibaleh L2 ; Abdolahi Z3 ; Nadri H3 ; Foroumadi A2, 4 ; Ebrahimi SES1, 4 ; Khoobi M2, 5
Authors
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Authors Affiliations
  1. 1. Department of Medical Chemistry, School of Pharmacy, International Campus, Tehran University of Medical Science (IC-TUMS), Tehran, Iran
  2. 2. Biomaterials Group, Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, 1417614411, Iran
  3. 3. Department of Medicinal Chemistry, Faculty of pharmacy and Pharmaceutical Sciences Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
  4. 4. Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
  5. 5. Department of Pharmaceutical Biomaterials, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

Source: Journal of Sciences# Islamic Republic of Iran Published:2019

Abstract

Inhibition of acetylcholinesterase and butyrylcholinesterase (AChE and BuChE) as two major forms of cholinesterases (ChEs) is considered as the common approach for the treatment of Alzheimer's disease (AD). The present study was done to explore the anticholinesterase inhibition property of coumarin Mannich base derivatives. A series of cumarin Manich bases were synthesized (4a-h) through one-pot tri-component reaction in an environmentally friendly condition and evaluated against AChE and BuChE by Ellman's assay. Ligand-protein docking simulation was also performed for the most active compound 4a. Additionally, the criteria of drug likeness of the target compounds was predicted using SwissADME web service. All compounds exhibited weak to moderate inhibitory activity against both AChE and BuChE enzymes. Compound 4a containing p-tolyl piperazin group showed the best activity against AChE (42.4 % at 32 µM), while compound 4g bearing phenylpiperazine moiety was the best BuChE inhibitor (43.9% at 32 µM). Ligand-protein docking simulation also exhibited that the main part of compound 4a in ChE inhibitory activity is amine moiety. Moreover, the prediction of Lipinski's rule of five showed that most target compounds can cross the BBB and have properties that would make them likely orally active compounds in humans. This study suggested that the synthesized cumarin Manich bases with some more structural modifications may be considered as a potential compound to target AChE and BuChE. © 2019 National Research Center of Medical Sciences. All rights reserved.
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