Advertisement

Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Synthesis and evaluation of chromone-2-carboxamido-alkylamines as potent acetylcholinesterase inhibitors

Abstract

Alzheimer’s disease (AD) is considered one of the greatest global public burdens. Pathophysiology of AD is proposed to be associated with reduced levels of the neurotransmitter acetylcholine (ACh). Cholinesterase enzymes, namely acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) cleave ACh via hydrolysis. Cholinesterase inhibitors (ChEIs) are the main group of drugs currently used for the treatment of AD. Novel chromone-2-carboxamido-alkylamines (718) were designed, synthesized, and evaluated for cholinesterase inhibitory activity. The compounds exhibited potent AChE inhibitory activities at micromolar range (IC50 0.09–9.16 µM) and demonstrated weak BChE inhibitory activities (IC50 12.09–44.56 µM). Compound 14 (IC50 0.09 ± 0.02 µM) was the most potent AChEI in this series; it showed higher activity than the clinical used drug tacrine. Enzyme kinetic study suggested that 14 was an uncompetitive inhibitor. Molecular docking study revealed that 14 was a dual-binding site inhibitor. Compound 14 did not induce any concentration-related cytotoxic effect against SH-SY5Y cells. It also showed neuroprotective effect in the cell line. Chromone-2-carboxamido-alkylamines can be promising lead compounds for development of anti-Alzheimer’s agents.

This is a preview of subscription content, log in to check access.

Fig. 1
Scheme 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. Ahmed M, Rocha JB, Corrêa M, Mazzanti CM, Zanin RF, Morsch AL, Morsch VM, Schetinger MR (2006) Inhibition of two different cholinesterases by tacrine. Chem Biol Interact 162:165–171

  2. Baptista FI, Henriques AG, Silva AM, Wiltfang J, da Cruz e Silva OA (2014) Flavonoids as therapeutic compounds targeting key proteins involved in Alzheimer’s disease. ACS Chem Neurosci 5:83–92

  3. Bera K, Sarkar S, Biswas S, Maiti S, Jana U (2011) Iron-catalyzed synthesis of functionalized 2H-chromenes via intramolecular alkyne-carbonyl metathesis. J Org Chem 76:3539–3544

  4. Bourne Y, Taylor P, Marchot P (1995) Acetylcholinesterase inhibition by fasciculin: crystal structure of the complex. Cell 83:503–512

  5. Castro A, Martinez A (2001) Peripheral and dual binding site acetylcholinesterase inhibitors: implications in treatment of Alzheimer’s disease. Mini Rev Med Chem 1:267–272

  6. Chatonnet A, Lockridge O (1989) Comparison of butyrylcholinesterase and acetylcholinesterase. Biochem J 260:625–634

  7. Cokugras AN (2003) Butyrylcholinesterase: structure and physiological importance. Turk J Biochem 28:54–61

  8. Ellman GL, Courtney KD, Andres Jr V, Featherstone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharm 7:88–95

  9. Forli S, Huey R, Pique ME (2016) Computational protein-ligand docking and virtual drug screening with the AutoDock suite. Nat Protoc 11:905–919

  10. Grazul M, Budzisz E (2009) Biological activity of metal ions complexes of chromones, coumarins and flavones. Coord Chem Rev 253:2588–2598

  11. Greenblatt HM, Kryger G, Lewis T, Silman I, Sussman JL (1999) Structure of acetylcholinesterase complexed with (-)-galanthamine at 2.3 Å resolution. FEBS Lett 463:321–326

  12. Greig NH, Lahiri DK, Sambamurti K (2002) Butyrylcholinesterase: an important new target in Alzheimer’s disease therapy. Int Psychogeriatr 14:77–91

  13. Hardy J, Selkoe JD (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356

  14. Kamal MA, Greig NH, Alhomida AS, Al-Jafari AA (2000) Kinetics of human acetylcholinesterase inhibition by the novel experimental Alzheimer therapeutic agent, tolserine. Biochem Pharm 60:561–570

  15. Lee K (2008) Computational study for protein-protein docking using global optimization and empirical potentials. Int J Mol Sci 9:65–77

  16. Liston DR, Nielsen JA, Villalobos A, Chapin D, Jones SB, Hubbard ST, Shalaby IA, Ramirez A, Nason D, White WF (2004) Pharmacology of selective acetylcholinesterase inhibitors: implications for use in Alzheimer’s disease. Eur J Pharm 486:9–17

  17. Liu Q, Qiang X, Li Y, Sang Z, Li Y, Tan Z, Deng Y (2015) Design, synthesis and evaluation of chromone-2-carboxamido-alkylbenzylamines as multifunctional agents for the treatment of Alzheimer’s disease. Bioorg Med Chem 23:911–923

  18. Luo W, Chen Y, Wang T, Hong C, Chang LP, Chang CC, Yang YC, Xie SQ, Wang CJ (2016) Design, synthesis and evaluation of novel 7-aminoalkyl-substituted flavonoid derivatives with improved cholinesterase inhibitory activities. Bioorg Med Chem 24:672–680

  19. Mayeux R, Sano M (1999) Treatment of Alzheimer’s disease. N. Engl J Med 341:1670–1679

  20. Mehta M, Adem A, Sabbagh M (2012) New acetylcholinesterase inhibitors for Alzheimer’s disease. Int J Alzheimers Dis 2012:1–8

  21. Nochi S, Asakawa N, Sato T (1995) Kinetic study on the inhibition of acetylcholinesterase by 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidinehydrochloride (E2020). Biol Pharm Bull 18:1145–1147

  22. Pourshojaei Y, Gouranourimi A, Hekmat S, Asadipour A, Rahmani-Nezhad S, Moradi A, Nadri H, Moghadam FH, Emami S, Foroumadi A, Shafiee (2015) A Design, synthesis and anticholinesterase activity of novel benzylidenechroman-4-ones bearing cyclic amine side chain. Eur J Med Chem 97:181–189

  23. Rogers SL, Friedhoff LT (1998) Long-term efficacy and safety of donepezil in the treatment of Alzheimer’s disease: an interim analysis of the results of a US multicentre open label extension study. Eur Neuropsychopharmacol 8:67–75

  24. Sang Z, Qiang X, Li Y, Xu R, Cao Z, Song Q, Wang T, Zhang X, Liu H, Tan Z, Deng Y (2017) Design, synthesis and evaluation of scutellarein-O-acetamidoalkylbenzylamines as potential multifunctional agents for the treatment of Alzheimer’s disease. Eur J Med Chem 28:307–323

  25. Sugimoto H, Yamanishi Y, Iimura Y, Kawakami Y (2000) Donepezil hydrochloride (E2020) and other acetylcholinesterase inhibitors. Curr Med Chem 7:303–339

  26. Tang BL, Kumar R (2008) Biomarkers of mild cognitive impairment and Alzheimer’s disease. Ann Acad Med Singap 37:406–410

  27. Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J Comput Chem 31:455–461

  28. Walenzyk T, Carola C, Buchholz H, König B (2005) Chromone derivatives which bind to human hair. Tetrahedron 61:7366–7377

  29. Xie HR, Hu LS, Li GY (2010) SH-SY5Y human neuroblastoma cell line: In vitro cell model of dopaminergic neurons in Parkinson’s disease. Chin Med J 123:1086–1092

  30. Yiannopoulou KG, Papageorgiou SG (2013) Current and future treatments for Alzheimer’s disease. Ther Adv Neurol Disord 6:19–33

Download references

Acknowledgements

We would like to thank Prince of Songkla University (Grant No. PHA590412S) and the University of Malaya (UMRG: RP037D-17AFR) for financial support of this study. The authors would like to thank Miss Maria Mullet for providing linguistic proofreading for the manuscript.

Author information

Correspondence to Luelak Lomlim.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Suwanhom, P., Nualnoi, T., Khongkow, P. et al. Synthesis and evaluation of chromone-2-carboxamido-alkylamines as potent acetylcholinesterase inhibitors. Med Chem Res 29, 564–574 (2020). https://doi.org/10.1007/s00044-020-02508-5

Download citation

Keywords

  • Chromone
  • Acetylcholinesterase inhibitors
  • Neuroprotective
  • Molecular docking