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

Author(s): Shahrzad Ghafary, Hamid Nadri, Mohammad Mahdavi, Alireza Moradi, Tahmineh Akbarzadeh, Mohammad Sharifzadeh, Najmeh Edraki, Farshad Homayouni Moghadam, Mohsen Amini*.

Journal Name: Letters in Drug Design & Discovery

Volume 17 , Issue 8 , 2020

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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.

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Article Details

Year: 2020
Page: [965 - 982]
Pages: 18
DOI: 10.2174/1570180817666191224094049
Price: $95

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