Flavones and flavanones as achetylcholinesterase inhibitors: the structure-activity relationship and molecular docking studies

Huynh Thi Kim Chi, Hoang-Phuc Nguyen, Hoàng Thị Kim Dung
Author affiliations

Authors

  • Huynh Thi Kim Chi Institute of Chemical Technology – VAST, 1 Mac Dinh Chi Str., Dist.1, Hochiminh city, VietnamGraduate University of Science and Technology – VAST, 18 Hoang Quoc Viet Str., Cau Giay Dist., Hanoi, Vietnam
  • Hoang-Phuc Nguyen Institute of Chemical Technology – VAST, 1 Mac Dinh Chi Str., Dist.1, Hochiminh city, Vietnam Ton Duc Thang University, 19 Nguyen Huu Tho, Dist. 7, Hochiminh city, Vietnam
  • Hoàng Thị Kim Dung Institute of Chemical Technology – VAST, 1 Mac Dinh Chi Str., Dist.1, Hochiminh city, Vietnam Graduate University of Science and Technology – VAST, 18 Hoang Quoc Viet Str., Cau Giay Dist., Hanoi, Vietnam https://orcid.org/0000-0002-9369-8051

DOI:

https://doi.org/10.15625/2525-2518/59/4/15487

Keywords:

flavones, flavanones, achetylcholinesterase, structure-activity relationship, molecular docking

Abstract

Discovering 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.

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References

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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. https://doi.org/10.1007/s12640-019-00142-7.">

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Published

13-08-2021

How to Cite

[1]
H. T. K. Chi, H.-P. Nguyen, and H. T. K. Dung, “Flavones and flavanones as achetylcholinesterase inhibitors: the structure-activity relationship and molecular docking studies”, Vietnam J. Sci. Technol., vol. 59, no. 4, pp. 441–450, Aug. 2021.

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Section

Natural Products