Generic placeholder image

Letters in Drug Design & Discovery


ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Research Article

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 and Mohsen Amini*

Volume 17, Issue 8, 2020

Page: [965 - 982] Pages: 18

DOI: 10.2174/1570180817666191224094049

Price: $65


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.

Graphical Abstract
Ghanei-Nasab, S.; Khoobi, M.; Hadizadeh, F.; Marjani, A.; Moradi, A.; Nadri, H.; Emami, S.; Foroumadi, A.; Shafiee, A. Synthesis and anticholinesterase activity of coumarin-3-carboxamides bearing tryptamine moiety. Eur. J. Med. Chem., 2016, 121, 40-46.
[] [PMID: 27214510]
Khoobi, M.; Alipour, M.; Sakhteman, A.; Nadri, H.; Moradi, A.; Ghandi, M.; Emami, S.; Foroumadi, A.; Shafiee, A. Design, synthesis, biological evaluation and docking study of 5-oxo-4,5-dihydropyrano[3,2-c]chromene derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors. Eur. J. Med. Chem., 2013, 68, 260-269.
[] [PMID: 23988409]
Mostofi, M.; Mohammadi Ziarani, G.; Mahdavi, M.; Moradi, A.; Nadri, H.; Emami, S.; Alinezhad, H.; Foroumadi, A.; Shafiee, A. Synthesis and structure-activity relationship study of benzofuran-based chalconoids bearing benzylpyridinium moiety as potent acetylcholinesterase inhibitors. Eur. J. Med. Chem., 2015, 103, 361-369.
[] [PMID: 26363872]
Terry, A.V., Jr; Buccafusco, J.J. The cholinergic hypothesis of age and Alzheimer’s disease-related cognitive deficits: recent challenges and their implications for novel drug development. J. Pharmacol. Exp. Ther., 2003, 306(3), 821-827.
[] [PMID: 12805474]
Hariri, R.; Afshar, Z.; Mahdavi, M.; Safavi, M.; Saeedi, M.; Najafi, Z.; Sabourian, R.; Karimpour-Razkenari, E.; Edraki, N.; Moghadam, F.H.; Shafiee, A.; Khanavi, M.; Akbarzadeh, T. Novel Tacrine-based pyrano[3′,4′:5,6]pyrano[2,3-b]quinolinones: Synthesis and cholinesterase inhibitory activity. Arch. Pharm. (Weinheim), 2016, 349(12), 915-924.
[] [PMID: 27910192]
Najafi, Z.; Saeedi, M.; Mahdavi, M.; Sabourian, R.; Khanavi, M.; Tehrani, M.B.; Moghadam, F.H.; Edraki, N.; Karimpor-Razkenari, E.; Sharifzadeh, M.; Foroumadi, A.; Shafiee, A.; Akbarzadeh, T. Design and synthesis of novel anti-Alzheimer’s agents: Acridine-chromenone and quinoline-chromenone hybrids. Bioorg. Chem., 2016, 67, 84-94.
[] [PMID: 27289559]
Talesa, V.N. Acetylcholinesterase in Alzheimer’s disease. Mech. Ageing Dev., 2001, 122(16), 1961-1969.
[] [PMID: 11589914]
Massoulié, J.; Pezzementi, L.; Bon, S.; Krejci, E.; Vallette, F-M. Molecular and cellular biology of cholinesterases. Prog. Neurobiol., 1993, 41(1), 31-91.
[] [PMID: 8321908]
Lane, R.M.; Potkin, S.G.; Enz, A. Targeting acetylcholinesterase and butyrylcholinesterase in dementia. Int. J. Neuropsychopharmacol., 2006, 9(1), 101-124.
[] [PMID: 16083515]
Greig, N.H.; Utsuki, T.; Yu, Q.; Zhu, X.; Holloway, H.W.; Perry, T.; Lee, B.; Ingram, D.K.; Lahiri, D.K. A new therapeutic target in Alzheimer’s disease treatment: attention to butyrylcholinesterase. Curr. Med. Res. Opin., 2001, 17(3), 159-165.
[] [PMID: 11900310]
Macdonald, I.R.; Rockwood, K.; Martin, E.; Darvesh, S. Cholinesterase inhibition in Alzheimer’s disease: is specificity the answer? J. Alzheimers Dis., 2014, 42(2), 379-384.
[] [PMID: 24898642]
Rahim, F.; Javed, M.T.; Ullah, H.; Wadood, A.; Taha, M.; Ashraf, M.; Qurat-ul-Ain, M.; Khan, M.A.; Khan, F.; Mirza, S.; Khan, K.M. Synthesis, molecular docking, acetylcholinesterase and butyrylcholinesterase inhibitory potential of thiazole analogs as new inhibitors for Alzheimer disease. Bioorg. Chem., 2015, 62, 106-116.
[] [PMID: 26318401]
Meena, P.; Nemaysh, V.; Khatri, M.; Manral, A.; Luthra, P.M.; Tiwari, M. Synthesis, biological evaluation and molecular docking study of novel piperidine and piperazine derivatives as multi-targeted agents to treat Alzheimer’s disease. Bioorg. Med. Chem., 2015, 23(5), 1135-1148.
[] [PMID: 25624107]
Edraki, N.; Firuzi, O.; Foroumadi, A.; Miri, R.; Madadkar-Sobhani, A.; Khoshneviszadeh, M.; Shafiee, A. Phenylimino-2H-chromen-3-carboxamide derivatives as novel small molecule inhibitors of β-secretase (BACE1). Bioorg. Med. Chem., 2013, 21(8), 2396-2412.
[] [PMID: 23480856]
Arab, S.; Sadat-Ebrahimi, S.E.; Mohammadi-Khanaposhtani, M.; Moradi, A.; Nadri, H.; Mahdavi, M.; Moghimi, S.; Asadi, M.; Firoozpour, L.; Pirali-Hamedani, M.; Shafiee, A.; Foroumadi, A. Synthesis and Evaluation of chroman-4-one linked to n-benzyl pyridinium derivatives as new acetylcholinesterase inhibitors. Arch. Pharm. (Weinheim), 2015, 348(9), 643-649.
[] [PMID: 26192069]
Baharloo, F.; Moslemin, M.H.; Nadri, H.; Asadipour, A.; Mahdavi, M.; Emami, S.; Firoozpour, L.; Mohebat, R.; Shafiee, A.; Foroumadi, A. Benzofuran-derived benzylpyridinium bromides as potent acetylcholinesterase inhibitors. Eur. J. Med. Chem., 2015, 93, 196-201.
[] [PMID: 25681712]
Dougherty, D.A.; Stauffer, D.A. Acetylcholine binding by a synthetic receptor: implications for biological recognition. Science, 1990, 250(4987), 1558-1560.
[] [PMID: 2274786]
Najafi, Z.; Mahdavi, M.; Saeedi, M.; Karimpour-Razkenari, E.; Asatouri, R.; Vafadarnejad, F.; Moghadam, F.H.; Khanavi, M.; Sharifzadeh, M.; Akbarzadeh, T. Novel tacrine-1,2,3-triazole hybrids: In vitro, in vivo biological evaluation and docking study of cholinesterase inhibitors. Eur. J. Med. Chem., 2017, 125, 1200-1212.
[] [PMID: 27863370]
Sussman, J.L.; Harel, M.; Frolow, F.; Oefner, C.; Goldman, A.; Toker, L.; Silman, I. Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein. Science, 1991, 253(5022), 872-879.
[] [PMID: 1678899]
Bartolini, M.; Bertucci, C.; Cavrini, V.; Andrisano, V. β-Amyloid aggregation induced by human acetylcholinesterase: inhibition studies. Biochem. Pharmacol., 2003, 65(3), 407-416.
[] [PMID: 12527333]
De Ferrari, G.V.; Canales, M.A.; Shin, I.; Weiner, L.M.; Silman, I.; Inestrosa, N.C. A structural motif of acetylcholinesterase that promotes amyloid β-peptide fibril formation. Biochemistry, 2001, 40(35), 10447-10457.
[] [PMID: 11523986]
Pera, M.; Martínez-Otero, A.; Colombo, L.; Salmona, M.; Ruiz-Molina, D.; Badia, A.; Clos, M.V. Acetylcholinesterase as an amyloid enhancing factor in PrP82-146 aggregation process. Mol. Cell. Neurosci., 2009, 40(2), 217-224.
[] [PMID: 19038345]
Piazzi, L.; Rampa, A.; Bisi, A.; Gobbi, S.; Belluti, F.; Cavalli, A.; Bartolini, M.; Andrisano, V.; Valenti, P.; Recanatini, M. 3-(4-[[Benzyl(methyl)amino]methyl]phenyl)-6,7-dimethoxy-2H-2-chromenone (AP2238) inhibits both acetylcholinesterase and acetylcholinesterase-induced β-amyloid aggregation: a dual function lead for Alzheimer’s disease therapy. J. Med. Chem., 2003, 46(12), 2279-2282.
[] [PMID: 12773032]
Castro, A.; Martinez, A. Peripheral and dual binding site acetylcholinesterase inhibitors: implications in treatment of Alzheimer’s disease. Mini Rev. Med. Chem., 2001, 1(3), 267-272.
[] [PMID: 12369973]
Li, Y.P.; Ning, F.X.; Yang, M.B.; Li, Y.C.; Nie, M.H.; Ou, T.M.; Tan, J.H.; Huang, S.L.; Li, D.; Gu, L.Q.; Huang, Z.S. Syntheses and characterization of novel oxoisoaporphine derivatives as dual inhibitors for cholinesterases and amyloid beta aggregation. Eur. J. Med. Chem., 2011, 46(5), 1572-1581.
[] [PMID: 21367493]
Rosini, M.; Andrisano, V.; Bartolini, M.; Bolognesi, M.L.; Hrelia, P.; Minarini, A.; Tarozzi, A.; Melchiorre, C. Rational approach to discover multipotent anti-Alzheimer drugs. J. Med. Chem., 2005, 48(2), 360-363.
[] [PMID: 15658850]
Rosini, M.; Simoni, E.; Bartolini, M.; Cavalli, A.; Ceccarini, L.; Pascu, N.; McClymont, D.W.; Tarozzi, A.; Bolognesi, M.L.; Minarini, A.; Tumiatti, V.; Andrisano, V.; Mellor, I.R.; Melchiorre, C. Inhibition of acetylcholinesterase, β-amyloid aggregation, and NMDA receptors in Alzheimer’s disease: a promising direction for the multi-target-directed ligands gold rush. J. Med. Chem., 2008, 51(15), 4381-4384.
[] [PMID: 18605718]
Khoobi, M.; Ghanoni, F.; Nadri, H.; Moradi, A.; Pirali Hamedani, M.; Homayouni Moghadam, F.; Emami, S.; Vosooghi, M.; Zadmard, R.; Foroumadi, A.; Shafiee, A. New tetracyclic tacrine analogs containing pyrano[2,3-c]pyrazole: efficient synthesis, biological assessment and docking simulation study. Eur. J. Med. Chem., 2015, 89, 296-303.
[] [PMID: 25462245]
Luo, X-T.; Wang, C-M.; Liu, Y.; Huang, Z-G. New multifunctional melatonin-derived benzylpyridinium bromides with potent cholinergic, antioxidant, and neuroprotective properties as innovative drugs for Alzheimer’s disease. Eur. J. Med. Chem., 2015, 103, 302-311.
[] [PMID: 26363866]
Zha, G-F.; Zhang, C-P.; Qin, H-L.; Jantan, I.; Sher, M.; Amjad, M.W.; Hussain, M.A.; Hussain, Z.; Bukhari, S.N.A. Biological evaluation of synthetic α,β-unsaturated carbonyl based cyclohexanone derivatives as neuroprotective novel inhibitors of acetylcholinesterase, butyrylcholinesterase and amyloid-β aggregation. Bioorg. Med. Chem., 2016, 24(10), 2352-2359.
[] [PMID: 27083471]
Najafi, Z.; Mahdavi, M.; Safavi, M.; Saeedi, M.; Alinezhad, H.; Pordeli, M.; Ardestani, S.K.; Shafiee, A.; Foroumadi, A.; Akbarzadeh, T. Synthesis and in vitro cytotoxic activity of novel triazole‐isoxazole derivatives. J. Heterocycl. Chem., 2015, 52, 1743-1747.
Saeedi, M.; Safavi, M.; Karimpour-Razkenari, E.; Mahdavi, M.; Edraki, N.; Moghadam, F.H.; Khanavi, M.; Akbarzadeh, T. Synthesis of novel chromenones linked to 1,2,3-triazole ring system: Investigation of biological activities against Alzheimer’s disease. Bioorg. Chem., 2017, 70, 86-93.
[] [PMID: 27914694]
Iman, K.; Mirza, M.U.; Mazhar, N.; Vanmeert, M.; Irshad, I.; Kamal, M.A. In silico structure-based identification of novel acetylcholinesterase inhibitors against Alzheimer’s disease. CNS Neurol. Disord. Drug Targets, 2018, 17(1), 54-68.
[] [PMID: 29336270]
Alugoju, P. Effect of Short-term quercetin, caloric restriction and combined treatment on age-related oxidative stress markers in the rat cerebral Cortex CNS Neurol. Disord., 2018, 17 pp, 119-131.
Farhat, S.M.; Ahmed, T. Aluminum suppresses effect of nicotine on gamma oscillations (20-40 Hz) in mouse hippocampal slices. CNS Neurol. Disord. Drug Targets, 2018, 17(6), 404-411.
[] [PMID: 29921211]
Bais, S.; Kumari, R.; Prashar, Y. Ameliorative effect of trans-sinapic acid and its protective role in cerebral hypoxia in aluminium chloride induced dementia of Alzheimer’s type. CNS Neurol. Disord. Drug Targets, 2018, 17(2), 144-154.
[] [PMID: 29521253]
Espinoza, L.C.; Vacacela, M.; Clares, B.; Garcia, M.L.; Fabrega, M-J.; Calpena, A.C. Development of a nasal donepezil-loaded microemulsion for the treatment of Alzheimer’s Disease: in vitro and ex vivo characterization. CNS Neurol. Disord. Drug Targets, 2018, 17(1), 43-53.
[] [PMID: 29299992]
Kamal, M.A.; Shakil, S.; Nawaz, M.S.; Yu, Q.S.; Tweedie, D.; Tan, Y.; Qu, X.; Greig, N.H.Q.U.X.; Greig, N.H. Inhibition of Butyrylcholinesterase with Fluorobenzylcymserine, an experimental Alzheimer’s drug candidate: Validation of enzoinformatics results by classical and innovative enzyme kinetic analyses. CNS Neurol. Disord. Drug Targets, 2017, 16(7), 820-827.
[] [PMID: 28176640]
Ellman, G.L.; Courtney, K.D.; Andres, V., Jr; Feather-Stone, R.M. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharmacol., 1961, 7, 88-95.
[] [PMID: 13726518]
Mohammadi-Khanaposhtani, M.; Saeedi, M.; Zafarghandi, N.S.; Mahdavi, M.; Sabourian, R.; Razkenari, E.K.; Alinezhad, H.; Khanavi, M.; Foroumadi, A.; Shafiee, A.; Akbarzadeh, T. Potent acetylcholinesterase inhibitors: design, synthesis, biological evaluation, and docking study of acridone linked to 1,2,3-triazole derivatives. Eur. J. Med. Chem., 2015, 92, 799-806.
[] [PMID: 25636055]
Gordon, J.; Amini, S.; White, M.K. General overview of neuronal cell culture. Methods Mol. Biol., 2013, 1078, 1-8.
[] [PMID: 23975816]
Trott, O.; Olson, A.J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461.
[PMID: 19499576]
Asadi, F.; Jamshidi, A.H.; Khodagholi, F.; Yans, A.; Azimi, L.; Faizi, M.; Vali, L.; Abdollahi, M.; Ghahremani, M.H.; Sharifzadeh, M. Reversal effects of crocin on amyloid β-induced memory deficit: Modification of autophagy or apoptosis markers. Pharmacol. Biochem. Behav 2015, 139(P T A), 47-58.
Morris, R. Developments of a water-maze procedure for studying spatial learning in the rat. J. Neurosci. Methods, 1984, 11(1), 47-60.
[] [PMID: 6471907]

Rights & Permissions Print Export Cite as
© 2023 Bentham Science Publishers | Privacy Policy