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Design, synthesis, and evaluation of novel cinnamic acid-tryptamine hybrid for inhibition of acetylcholinesterase and butyrylcholinesterase.
Daru. 2020 Dec; 28(2):463-477.DARU

Abstract

BACKGROUND

Acetylcholine deficiencies in hippocampus and cortex, aggregation of β-amyloid, and β-secretase over activity have been introduced as main reasons in pathogenesis of Alzheimer's disease.

METHODS

Colorimetric Ellman's method was used for determination of IC50 value in AChE and BChE inhibitory activity. The kinetic studies, neuroprotective and β-secretase inhibitory activities, evaluation of inhibitory potency on β-amyloid (Aβ) aggregations induced by AChE, and docking study were performed for prediction of the mechanism of action.

RESULT AND DISCUSSION

A new series of cinnamic acids-tryptamine hybrid was designed, synthesized, and evaluated as dual cholinesterase inhibitors. These compounds demonstrated in-vitro inhibitory activities against acetyl cholinesterase (AChE) and butyryl cholinesterase (BChE). Among of these synthesized compounds, (E)-N-(2-(1H-indol-3-yl)ethyl)-3-(3,4-dimethoxyphenyl)acrylamide (5q) demonstrated the most potent AChE inhibitory activity (IC50 = 11.51 μM) and (E)-N-(2-(1H-indol-3-yl)ethyl)-3-(2-chlorophenyl)acrylamide (5b) were the best anti-BChE (IC50 = 1.95 μM) compounds. In addition, the molecular modeling and kinetic studies depicted 5q and 5b were mixed type inhibitor and bound with both the peripheral anionic site (PAS) and catalytic sites (CAS) of AChE and BChE. Moreover, compound 5q showed mild neuroprotective in PC12 cell line and weak β-secretase inhibitory activities. This compound also inhibited aggregation of β-amyloid (Aβ) in self-induced peptide aggregation test at concentration of 10 μM.

CONCLUSION

It is worth noting that both the kinetic study and the molecular modeling of 5q and 5b depicted that these compounds simultaneously interacted with both the catalytic active site and the peripheral anionic site of AChE and BChE. These findings match with those resulted data from the enzyme inhibition assay. Graphical abstract A new series of cinnamic-derived acids-tryptamine hybrid derivatives were designed, synthesized and evaluated as butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) inhibitors and neuroprotective agents. Compound 5b and 5q, as the more potent compounds, interacted with both the peripheral site and the choline binding site having mixed type inhibition. Results suggested that derivatives have a therapeutic potential for the treatment of AD.

Authors+Show Affiliations

Department of Medicinal Chemistry, Faculty of Pharmacy and Drug Design & Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran.Department of Medicinal Chemistry, Faculty of Pharmacy and Drug Design & Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran.Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.Department of Medicinal Chemistry, Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.Department of Medicinal Chemistry, Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.Department of Medicinal Chemistry, Faculty of Pharmacy and Drug Design & Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran.Department of Medicinal Chemistry, School of Pharmacy, Hamedan University of Medical Sciences, Hamedan, Iran.Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Science, Shiraz, Iran.Department of Cellular Biotechnology at Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran.Department of Medicinal Chemistry, Faculty of Pharmacy and Drug Design & Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran. moamini@tums.ac.ir.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32372339

Citation

Ghafary, Shahrzad, et al. "Design, Synthesis, and Evaluation of Novel Cinnamic Acid-tryptamine Hybrid for Inhibition of Acetylcholinesterase and Butyrylcholinesterase." Daru : Journal of Faculty of Pharmacy, Tehran University of Medical Sciences, vol. 28, no. 2, 2020, pp. 463-477.
Ghafary S, Ghobadian R, Mahdavi M, et al. Design, synthesis, and evaluation of novel cinnamic acid-tryptamine hybrid for inhibition of acetylcholinesterase and butyrylcholinesterase. Daru. 2020;28(2):463-477.
Ghafary, S., Ghobadian, R., Mahdavi, M., Nadri, H., Moradi, A., Akbarzadeh, T., Najafi, Z., Sharifzadeh, M., Edraki, N., Moghadam, F. H., & Amini, M. (2020). Design, synthesis, and evaluation of novel cinnamic acid-tryptamine hybrid for inhibition of acetylcholinesterase and butyrylcholinesterase. Daru : Journal of Faculty of Pharmacy, Tehran University of Medical Sciences, 28(2), 463-477. https://doi.org/10.1007/s40199-020-00346-9
Ghafary S, et al. Design, Synthesis, and Evaluation of Novel Cinnamic Acid-tryptamine Hybrid for Inhibition of Acetylcholinesterase and Butyrylcholinesterase. Daru. 2020;28(2):463-477. PubMed PMID: 32372339.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Design, synthesis, and evaluation of novel cinnamic acid-tryptamine hybrid for inhibition of acetylcholinesterase and butyrylcholinesterase. AU - Ghafary,Shahrzad, AU - Ghobadian,Roshanak, AU - Mahdavi,Mohammad, AU - Nadri,Hamid, AU - Moradi,Alireza, AU - Akbarzadeh,Tahmineh, AU - Najafi,Zahra, AU - Sharifzadeh,Mohammad, AU - Edraki,Najmeh, AU - Moghadam,Farshad Homayouni, AU - Amini,Mohsen, Y1 - 2020/05/05/ PY - 2019/04/18/received PY - 2020/04/03/accepted PY - 2020/5/7/pubmed PY - 2021/8/28/medline PY - 2020/5/7/entrez KW - Alzheimer’s disease KW - Butyrylcholinesterase KW - Cinnamic acid derivatives KW - Docking study KW - In-vitro assay SP - 463 EP - 477 JF - Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences JO - Daru VL - 28 IS - 2 N2 - BACKGROUND: Acetylcholine deficiencies in hippocampus and cortex, aggregation of β-amyloid, and β-secretase over activity have been introduced as main reasons in pathogenesis of Alzheimer's disease. METHODS: Colorimetric Ellman's method was used for determination of IC50 value in AChE and BChE inhibitory activity. The kinetic studies, neuroprotective and β-secretase inhibitory activities, evaluation of inhibitory potency on β-amyloid (Aβ) aggregations induced by AChE, and docking study were performed for prediction of the mechanism of action. RESULT AND DISCUSSION: A new series of cinnamic acids-tryptamine hybrid was designed, synthesized, and evaluated as dual cholinesterase inhibitors. These compounds demonstrated in-vitro inhibitory activities against acetyl cholinesterase (AChE) and butyryl cholinesterase (BChE). Among of these synthesized compounds, (E)-N-(2-(1H-indol-3-yl)ethyl)-3-(3,4-dimethoxyphenyl)acrylamide (5q) demonstrated the most potent AChE inhibitory activity (IC50 = 11.51 μM) and (E)-N-(2-(1H-indol-3-yl)ethyl)-3-(2-chlorophenyl)acrylamide (5b) were the best anti-BChE (IC50 = 1.95 μM) compounds. In addition, the molecular modeling and kinetic studies depicted 5q and 5b were mixed type inhibitor and bound with both the peripheral anionic site (PAS) and catalytic sites (CAS) of AChE and BChE. Moreover, compound 5q showed mild neuroprotective in PC12 cell line and weak β-secretase inhibitory activities. This compound also inhibited aggregation of β-amyloid (Aβ) in self-induced peptide aggregation test at concentration of 10 μM. CONCLUSION: It is worth noting that both the kinetic study and the molecular modeling of 5q and 5b depicted that these compounds simultaneously interacted with both the catalytic active site and the peripheral anionic site of AChE and BChE. These findings match with those resulted data from the enzyme inhibition assay. Graphical abstract A new series of cinnamic-derived acids-tryptamine hybrid derivatives were designed, synthesized and evaluated as butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) inhibitors and neuroprotective agents. Compound 5b and 5q, as the more potent compounds, interacted with both the peripheral site and the choline binding site having mixed type inhibition. Results suggested that derivatives have a therapeutic potential for the treatment of AD. SN - 2008-2231 UR - https://www.unboundmedicine.com/medline/citation/32372339/Design_synthesis_and_evaluation_of_novel_cinnamic_acid_tryptamine_hybrid_for_inhibition_of_acetylcholinesterase_and_butyrylcholinesterase_ L2 - https://darujps.biomedcentral.com/articles/10.1007/s40199-020-00346-9 DB - PRIME DP - Unbound Medicine ER -