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Anticholinesterase Activity of Cinnamic Acids Derivatives: In Vitro, In Vivo Biological Evaluation, and Docking Study

[ Vol. 17 , Issue. 8 ]

Author(s):

Shahrzad Ghafary, Hamid Nadri, Mohammad Mahdavi, Alireza Moradi, Tahmineh Akbarzadeh, Mohammad Sharifzadeh, Najmeh Edraki, Farshad Homayouni Moghadam and Mohsen Amini*   Pages 965 - 982 ( 18 )

Abstract:


Background: Acetylcholine deficiency in the hippocampus and cortex, aggregation of amyloid-beta, and beta-secretase overactivity have been introduced as the main reasons in the formation of Alzheimer’s disease.

Objective: A new series of cinnamic derived acids linked to 1-benzyl-1,2,3-triazole moiety were designed, synthesized, and evaluated for their acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities.

Methods: Colorimetric Ellman’s method was used for the determination of IC50% of AchE and BuChE inhibitory activity. The kinetic studies, neuroprotective activity, BACE1 inhibitory activity, evaluation of inhibitory potency on Aβ1-42 self-aggregation induced by AchE, and docking study were performed for studying the mechanism of action.

Results: Some of the synthesized compounds, compound 7b-4 ((E)-3-(3,4-dimethoxyphenyl)-N-((1- (4-fluorobenzyl)-1H-1,2,3-triazole-4-yl) methyl) acrylamide) depicted the most potent acetylcholinesterase inhibitory activities ( IC50 = 5.27 μM ) and compound 7a-1 (N- ( (1- benzyl- 1H- 1, 2, 3- triazole - 4-yl) methyl) cinnamamide) demonstrated the most potent butyrylcholinesterase inhibitory activities (IC50 = 1.75 μM). Compound 7b-4 showed neuroprotective and β-secretase (BACE1) inhibitory activitiy. In vivo studies of compound 7b-4 in Scopolamine-induced dysfunction confirmed memory improvement.

Conclusion: It should be noted that molecular modeling (compounds 7b-4 and 7a-1) and kinetic studies (compounds 7a-1 and 7b-4) showed that these synthesis compounds interacted simultaneously with both the catalytic site (CS) and peripheral anionic site (PAS) of AChE and BuChE.

Keywords:

Cholinesterase, Alzheimer’s disease, docking study, cinnamic acid derivatives, in vitro, in vivo assay.

Affiliation:

Department of Medicinal Chemistry, Faculty of Pharmacy, Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Department of Medicinal Chemistry, Faculty of Pharmacy, ShahidSadoughi University of Medical Sciences, Yazd, Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Science, Tehran, Department of Medicinal Chemistry, Faculty of Pharmacy, ShahidSadoughi University of Medical Sciences, Yazd, Department of Medicinal Chemistry, Faculty of Pharmacy, Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Science, Shiraz, Department of Cellular Biotechnology at Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Department of Medicinal Chemistry, Faculty of Pharmacy, Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran

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