FLAVONES AND FLAVANONES AS ACHETYLCHOLINESTERASE INHIBITORS: THE STRUCTURE-ACTIVITY RELATIONSHIP AND MOLECULAR DOCKING STUDIES
Keywords:flavones, flavanones, achetylcholinesterase, structure-activity relationship, molecular docking
AbstractDiscovering and developing drugs to treat Alzheimer's disease (AD) have been a crucial target for many decades. According to a large number of later studies, acetylcholinesterase (AChE) plays an important role in AD treatment. On the other hand, flavonoids are natural compounds that possessed a wide variety of bioactivities, including the inhibitory activity on AChE. In this study, we reported the structure and activity relationship of flavone and flavanone derivatives that semi-synthesized and synthesized from flower buds of Styphnolobium japonicum (Leguminosae) and citrus peels against AChE. The results showed that the introducing of the new functional groups that leads to increasing 3-folds better AChE inhibition of compound Q2 and Q4 than that of the original. The molecular docking study was investigated in order to illuminate the experimental results and find their binding modes.
Khan, M. T. H.; Orhan, I.; Şenol, F.; Kartal, M.; Şener, B.; Dvorská, M.; Šmejkal, K.; Šlapetová, T. - Cholinesterase inhibitory activities of some flavonoid derivatives and chosen xanthone and their molecular docking studies, Chem. Biol. Interact. 181 (3) (2009) 383-389. https://doi.org/10.1016/j.cbi.2009.06.024.
Shen, Y.; Zhang, J.; Sheng, R.; Dong, X.; He, Q.; Yang, B.; Hu, Y. - Synthesis and biological evaluation of novel flavonoid derivatives as dual binding acetylcholinesterase inhibitors, J. Enzyme Inhib. Med. Chem. 24 (2) (2009) 372-380. https://doi.org/10.1080/14756360802187885.
Kim, J. Y.; Lee, W. S.; Kim, Y. S.; Curtis-Long, M. J.; Lee, B. W.; Ryu, Y. B.; Park, K. H. - Isolation of cholinesterase-inhibiting flavonoids from Morus lhou, J. Agric. Food. Chem. 59 (9) (2011) 4589-96. https://doi.org/10.1021/jf200423g.
Henry, W.; Querfurth, H.; LaFerla, F. - Mechanisms of disease Alzheimer’s disease, New Engl. J. Med. 362 (2010) 329-344. https://doi.org/10.1056/NEJMra0909142.
Todd, S.; Barr, S.; Roberts, M.; Passmore, A. P. - Survival in dementia and predictors of mortality: a review, Int. J. Geriatr. Psychiatry 28 (11) (2013) 1109-1124. https://doi.org/10.1002/gps.3946.
Perry, E. K.; Perry, R.; Blessed, G.; Tomlinson, B. - Changes in brain cholinesterases in senile dementia of Alzheimer type, Neuropathol. Appl. Neurobiol. 4 (4) (1978) 273-277. https://doi.org/10.1111/j.1365-2990.1978.tb00545.x.
Davies, P.; Maloney, A. - Selective loss of central cholinergic neurons in Alzheimer's disease, Lancet 308 (8000) (1976) 1403. https://doi.org/10.1016/s0140-6736(76)91936-x.
Whitehouse, P. J.; Price, D. L.; Struble, R. G.; Clark, A. W.; Coyle, J. T.; Delon, M. R. - Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain, Science 215 (4537) (1982) 1237-1239. https://doi.org/10.1126/science.7058341.
Ciro, A.; Park, J.; Burkhard, G.; Yan, N.; Geula, C. - Biochemical differentiation of cholinesterases from normal and Alzheimer's disease cortex, Curr. Alzheimer Res. 9 (1) (2012) 138-143. https://doi.org/10.2174/156720512799015127.
Mushtaq, G.; H Greig, N.; A Khan, J.; A Kamal, M. - Status of acetylcholinesterase and butyrylcholinesterase in Alzheimer's disease and type 2 diabetes mellitus, CNS Neurol. Disord. Drug Targets 13 (8) (2014) 1432-1439. https://doi.org/10.2174/1871527313666141023141545.
Morsy, A.; Trippier, P. C. - Current and emerging pharmacological targets for the treatment of Alzheimer’s disease, J. Alzheimers Dis. 72 (s1) (2019) 145-176. https://doi.org/10.1111/joim.12959.
Sheng, R.; Lin, X.; Zhang, J.; Chol, K. S.; Huang, W.; Yang, B.; He, Q.; Hu, Y. - Design, synthesis and evaluation of flavonoid derivatives as potent AChE inhibitors, Bioorg. Med. Chem. 17 (18) (2009) 6692-6698. https://doi.org/10.1016/j.bmc.2009.07.072.
Rydberg, E. H.; Brumshtein, B.; Greenblatt, H. M.; Wong, D. M.; Shaya, D.; Williams, L. D.; Carlier, P. R.; Pang, Y.-P.; Silman, I.; Sussman, J. L. - Complexes of Alkylene-linked Tacrine dimers with Torpedo c alifornica acetylcholinesterase: Binding of Bis (5)-tacrine produces a dramatic rearrangement in the active-site gorge, J. Med. Chem. 49 (18) (2006) 5491-5500. https://doi.org/10.1021/jm060164b.
Bajda, M.; Guzior, N.; Ignasik, M.; Malawska, B. - Multi-target-directed ligands in Alzheimer's disease treatment, Curr. Med. Chem. 18 (32) (2011) 4949-4975. https://doi.org/10.2174/092986711797535245.
Seleem, D.; Pardi, V.; Murata, R. M. - Review of flavonoids: A diverse group of natural compounds with anti-Candida albicans activity in vitro, Arch. Oral Biol. 76 (2017) 76-83. https://doi.org/10.1016/j.archoralbio.2016.08.030.
Singh, A.; Kumar, S.; Bajpai, V.; Reddy, T. J.; Rameshkumar, K.; Kumar, B. - Structural characterization of flavonoid C‐and O‐glycosides in an extract of Adhatoda vasica leaves by liquid chromatography with quadrupole time‐of‐flight mass spectrometry, Rapid Commun. Mass Spectrom. 29 (12) (2015) 1095-1106. https://doi.org/10.1002/rcm.7202.
Butun, B.; Topcu, G.; Ozturk, T. - Recent advances on 3-hydroxyflavone derivatives: Structures and properties, Mini-Rev. Med. Chem. 18 (2) (2018) 98-103. https://doi.org/10.2174/1389557517666170425102827.
Sendrayaperumal, V.; Pillai, S. I.; Subramanian, S. - Design, synthesis and characterization of zinc–morin, a metal flavonol complex and evaluation of its antidiabetic potential in HFD–STZ induced type 2 diabetes in rats, Chem. Biol. Interact. 219 (2014) 9-17. https://doi.org/10.1016/j.cbi.2014.05.003.
Culhaoglu, B.; Capan, A.; Boga, M.; Ozturk, M.; Ozturk, T.; Topcu, G. - Antioxidant and anticholinesterase activities of some dialkylamino substituted 3-hydroxyflavone derivatives, Med. Chem. 13 (3) (2017) 254-259. https://doi.org/10.2174/1573406412666161104121642.
Mughal, E. U.; Sadiq, A.; Ashraf, J.; Zafar, M. N.; Sumrra, S. H.; Tariq, R.; Mumtaz, A.; Javid, A.; Khan, B. A.; Ali, A. - Flavonols and 4-thioflavonols as potential acetylcholinesterase and butyrylcholinesterase inhibitors: Synthesis, structure-activity relationship and molecular docking studies, Bioorg. Chem. 91 (2019) 103124. https://doi.org/10.1016/j.bioorg.2019.103124.
Airoldi, C.; La Ferla, B.; D'Orazio, G.; Ciaramelli, C.; Palmioli, A. - Flavonoids in the treatment of Alzheimer's and other neurodegenerative diseases, Curr. Med. Chem. 25 (27) (2018) 3228-3246. https://doi.org/10.2174/0929867325666180209132125.
Dourado, N. S.; dos Santos Souza, C.; de Almeida, M. M. A.; da Silva, A. B.; dos Santos, B. L.; Silva, V. D. A.; De Assis, A. M.; da Silva, J. S.; Souza, D. O.; Costa, M. d. F. D. - Neuroimmunomodulatory and Neuroprotective Effects of the Flavonoid Apigenin in in vitro Models of Neuroinflammation Associated With Alzheimer’s Disease, Front. Aging Neurosci. 12 (2020) 1-14. https://doi.org/10.3389/fnagi.2020.00119.
Hoang, T. K.-D.; Huynh, T. K.-C.; Nguyen, T.-D. - Synthesis, characterization, anti-inflammatory and anti-proliferative activity against MCF-7 cells of O-alkyl and O-acyl flavonoid derivatives, Bioorg. Chem. 63 (2015) 45-52. https://doi.org/10.1016/j.bioorg.2015.09.005.
Hoang, T. K.-D.; Huynh, T. K.-C.; Do, T. H.-T.; Nguyen, T.-D. - Mannich aminomethylation of flavonoids and anti-proliferative activity against breast cancer cell, Chem. Pap. 72 (6) (2018) 1399-1406. https://doi.org/doi.org/10.1007/s11696-018-0402-1.
Ellman, G. L.; Courtney, K. D.; Andres Jr, V.; Featherstone, R. M. - A new and rapid colorimetric determination of acetylcholinesterase activity, Biochem. Pharmacol. 7 (2) (1961) 88-95. https://doi.org/10.1016/0006-2952(61)90145-9.
Alper, P.; Erkisa, M.; Genckal, H. M.; Sahin, S.; Ulukaya, E.; Ari, F. - Synthesis, characterization, anticancer and antioxidant activity of new nickel (II) and copper (II) flavonoid complexes, J. Mol. Struct. 1196 (2019) 783-792. https://doi.org/10.1016/j.molstruc.2019.07.009.
Da Silva, W. M. B.; de Oliveira Pinheiro, S.; Alves, D. R.; de Menezes, J. E. S. A.; Magalhães, F. E. A.; Silva, F. C. O.; Silva, J.; Marinho, E. S.; de Morais, S. M. - Synthesis of Quercetin-Metal Complexes, In Vitro and In Silico Anticholinesterase and Antioxidant Evaluation, and In Vivo Toxicological and Anxiolitic Activities, Neurotox. Res. (2019) 1-11. https://doi.org/10.1007/s12640-019-00142-7.
How to Cite
Copyright (c) 2021 Vietnam Journal of Science and Technology
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Authors who publish with Vietnam Journal of Science and Technology agree with the following terms:
- The manuscript is not under consideration for publication elsewhere. When a manuscript is accepted for publication, the author agrees to automatic transfer of the copyright to the editorial office.
- The manuscript should not be published elsewhere in any language without the consent of the copyright holders. Authors have the right to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal’s published version of their work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
- Authors are encouraged to post their work online (e.g., in institutional repositories or on their websites) prior to or during the submission process, as it can lead to productive exchanges or/and greater number of citation to the to-be-published work (See The Effect of Open Access).