Medicinal Chemistry Research

, Volume 27, Issue 2, pp 520–530 | Cite as

Design, synthesis and biological evaluation of 2-Phenyl-4H-chromen-4-one derivatives as polyfunctional compounds against Alzheimer’s disease

  • Manjinder Singh
  • Maninder Kaur
  • Bhawna Vyas
  • Om Silakari
Original Research


Polyfunctional compounds comprise a novel class of therapeutic agents for the treatment of multi-factorial diseases. A series of 2-Phenyl-4H-chromen-4-one and its derivatives (5an) were designed, synthesized, and evaluated for their poly-functionality against acetylcholinestrase (AChE) and advanced glycation end products (AGEs) formation inhibitors against Alzheimer’s disease (AD). The screening results showed that most of them exhibited a significant ability to inhibit AChE AGEs formation with additional radical scavenging activity. Especially, 5m, 5b, and 5j displayed the greatest ability to inhibit AChE (IC50 = 8.0, 8.2, and 11.8 nM, respectively) and AGEs formation (IC50 = 55, 79, and 54 µM, respectively) with good antioxidant activity. Molecular docking studies explored the detailed interaction pattern with active, peripheral, and mid-gorge sites of AChE. These compounds, exhibiting such multiple pharmacological activities, can be further taken a lead for the development of potent drugs for the treatment of Alzheimer’s disease.


AChE inhibitor Alzheimer’s disease Antioxidants Flavonoids AGEs Flavone 





Alzheimer’s disease




Advanced glycation end products


Catalytic active site


Peripheral anionic site




Food and drug administration


Oxidative stress


Reactive oxygen species



Receptor for AGEs




Electron withdrawing groups



We acknowledge the financial support from the “Indian Council of Medical Research (ICMR)”, New Delhi, for providing us Senior Research Fellowships (ICMR-SRF); Award nos. BIC/11(11)/2014 and BIC/11(02)/2013.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

44_2017_2078_MOESM1_ESM.docx (639 kb)
Supplementary Information


  1. Lee J, Yu J, Son SH, Heo J, Kim T, An JY, Inn KS, Kim NJ (2016) A versatile approach to flavones via a one-pot Pd(II)-catalyzed dehydrogenation/oxidative boron-Heck coupling sequence of chromanones. Org Biomol Chem 14:777–784CrossRefPubMedGoogle Scholar
  2. Cabrera M, Simoens M, Falchi G, Lavaggi ML, Piro OE, Castellano EE, Vidal A, Azqueta A, Monge A, de Ceráin AL, Sagrera G, Seoane G, Cerecetto H, González M (2007) Synthetic chalcones, flavanones, and flavones as antitumoral agents: biological evaluation and structure–activity relationships. Bioorg Med Chem 15:3356–3367CrossRefPubMedGoogle Scholar
  3. Cárdenas M, Marder M, Blank VC, Roguin LP (2006) Antitumor activity of some natural flavonoids and synthetic derivatives on various human and murine cancer cell lines. Bioorg Med Chem 14:2966–2971CrossRefPubMedGoogle Scholar
  4. Narwal M, Haikarainen T, Fallarero A, Vuorela PM, Lehtio L (2013) Screening and structural analysis of flavones inhibiting tankyrases. J Med Chem 56:3507–3517CrossRefPubMedGoogle Scholar
  5. Lin YM, Zhou Y, Flavin MT, Zhou LM, Nie W, Chen FC (2002) Chalcones and flavonoids as anti-tuberculosis agents. Bioorg Med Chem 10:2795–2802CrossRefPubMedGoogle Scholar
  6. Dao TT, Chi YS, Kim J, Kim HP, Kim S, Park H (2004) Synthesis and inhibitory activity against COX-2 catalyzed prostaglandin production of chrysin derivatives. Bioorg Med Chem Lett 14:1165–1167CrossRefPubMedGoogle Scholar
  7. Fesen MR, Pommier Y, Leteurtre F, Hiroguchi S, Yung J, Kohn KW (1994) Inhibition of HIV-1 Integrase by flavones, caffeic acid phenethyl ester (Cape) and related compounds. Biochem Pharmacol 48:595–608CrossRefPubMedGoogle Scholar
  8. Baker W (1933) Molecular rearrangement of some o-acyloxyacetophenones and the mechanism of the production of 3-acylchromones. J Chem Soc 10:1381–1389CrossRefGoogle Scholar
  9. Bishop NA, Lu T, Yankner BA (2010) Neural mechanisms of ageing and cognitive decline. Nature 464:529–535CrossRefPubMedPubMedCentralGoogle Scholar
  10. Blois MS (1958) Antioxidant determinations by the use of a stable free radical. Nature 181:1199–1200CrossRefGoogle Scholar
  11. Bolognesi ML, Rosini M, Andrisano V, Bartolini M, Minarini A, Tumiatti V, Melchiorre C (2009) MTDL design strategy in the context of Alzheimer’s disease: from lipocrine to memoquin and beyond. Curr Pharm Des 15:601–613CrossRefPubMedGoogle Scholar
  12. Ellman GL, Courtney KD, Valentino A, Featherstone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88–95CrossRefPubMedGoogle Scholar
  13. Fang L, Kraus B, Lehmann J, Heilmann J, Zhang Y, Decker M (2008) Design and synthesis of tacrine-ferulic acid hybrids as multi-potent anti-Alzheimer drug candidates. Bioorg Med Chem Lett 18:2905–2909CrossRefPubMedGoogle Scholar
  14. Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shelley M, Perry JK, Shaw DE, Francis P, Shenkin PS (2004) Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 47:1739–1749CrossRefPubMedGoogle Scholar
  15. Glide (2010) Version 5.6. Schrodinger LLC, New YorkGoogle Scholar
  16. Jung M, Park M (2007) Acetylcholinesterase inhibition by flavonoids from Agrimonia pilosa. Molecules 12:2130–2139CrossRefPubMedGoogle Scholar
  17. Kim H, Park BS, Lee KG, Choi CY, Jang SS, Kim YH, Lee SE (2005) Effects of naturally occurring compounds on fibril formation and oxidative stress of beta-amyloid. J Agric Food Chem 53:8537–8541CrossRefPubMedGoogle Scholar
  18. Kryger G, Silman I, Sussman JL (1999) Structure of acetylcholinesterase complexed with E2020 (Aricept): implications for the design of new anti-Alzheimer drugs. Structure 7:297–307CrossRefPubMedGoogle Scholar
  19. Ligprep (2011) Version 2.5. Schrodinger LLC, New YorkGoogle Scholar
  20. Lim SS, Han SM, Kim SY, Bae YS, Kang IJ (2007) Isolation of acetylcholinesterase inhibitors from the flowers of chrysanthemum indicum linne. Food Sci Biotech 16:265–269Google Scholar
  21. Mahal HS, Venkataraman KJ (1934) Synthetical experiments in the chromone group. Part XIV. The action of sodamide on 1-acyloxy-2-acetonaphthones. J Chem Soc 56:1767–1769CrossRefGoogle Scholar
  22. Markesbery WR (1997) Oxidative stress hypothesis in Alzheimer’s disease. Free Radic Biol Med 23:134–147CrossRefPubMedGoogle Scholar
  23. Matsuura N, Aradate T, Sasaki C, Kojima H, Ohara M, Hasegawa J, Ubukata M (2002) Screening system for the maillard reaction inhibitor from natural product extracts. J Health Sci 48:520–526CrossRefGoogle Scholar
  24. Melo JB, Agostinho P, Oliveira CR (2003) Involvement of oxidative stress in the enhancement of acetylcholinesterase activity induced by amyloid beta-peptide. Neurosci Res 45:117–127CrossRefPubMedGoogle Scholar
  25. Morphy R, Rankovic Z (2005) Designed multiple ligands. An emerging drug discovery paradigm. J Med Chem 48:6523–6543CrossRefPubMedGoogle Scholar
  26. Münch Gl, Thome J, Foley P, Schinzel R, Riederer P (1997) Advanced glycation endproducts in ageing and Alzheimer’s disease. Brain Res Rev 23:134–143CrossRefPubMedGoogle Scholar
  27. Pi RB, Ye MZ, Cheng ZY, Liu PQ (2008) Univ Zhongshan (UZHO-C). Patent CN101284812-A, ChinaGoogle Scholar
  28. Prathapan A, Nampoothiri SV, Mini S, Raghu KG (2012) Antioxidant, antiglycation and inhibitory potential of Saraca ashoka flowers against the enzymes linked to type 2 diabetes and LDL oxidation. Eur Rev Med Pharmacol Sci 16:57–65PubMedGoogle Scholar
  29. Schmitt B, Bernhardt T, Moeller HJ, Heuser I, Frolich L (2004) Combination therapy in Alzheimer’s disease: a review of current evidence. CNS Drugs 18:827–844CrossRefPubMedGoogle Scholar
  30. Singh M, Kaur M, Kukreja H, Chugh R, Silakari O, Singh D (2013) Acetylcholinesterase inhibitors as Alzheimer therapy: from nerve toxins to neuroprotection. Eur J Med Chem 70:165–188CrossRefPubMedGoogle Scholar
  31. Singh M, Kaur M, Silakari O (2014) Flavones: an important scaffold for medicinal chemistry. Eur J Med Chem 84:206–239CrossRefPubMedGoogle Scholar
  32. Singh M, Kaur M, Chadha N, Silakari O (2016) Hybrids: a new paradigm to treat Alzheimer’s disease. Mol Divers 20:271–297CrossRefPubMedGoogle Scholar
  33. Yan SD, Chen X, Schmidt AM, Brett J, Godman G, Zou YS, Scott CW, Caputo C, Frappier T, Smith MA (1994) Glycated tau protein in Alzheimer disease: a mechanism for induction of oxidant stress. Proc Natl Acad Sci USA 91:7787–7791CrossRefPubMedPubMedCentralGoogle Scholar
  34. Yamagishi S, Takeuchi M, Inagaki Y, Nakamura K, Imaizumi T (2003) Role of advanced glycation end products (AGEs) and their receptor (RAGE) in the pathogenesis of diabetic microangiopathy. Int J Clin Pharmacol Res 23:129–134PubMedGoogle Scholar
  35. Youdim MB, Buccafusco JJ (2005) Multi-functional drugs for various CNS targets in the treatment of neurodegenerative disorders. Trends Pharmacol Sci 26:27–35CrossRefPubMedGoogle Scholar
  36. Zhu JT, Choi RC, Chu GK, Cheung AW, Gao QT, Li J, Jiang ZY, Dong TT, Tsim KW (2007) Flavonoids possess neuroprotective effects on cultured pheochromocytoma PC12 cells: a comparison of different flavonoids in activating estrogenic effect and in preventing beta-amyloid-induced cell death. J Agric Food Chem 55:2438–2445CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Manjinder Singh
    • 1
  • Maninder Kaur
    • 1
  • Bhawna Vyas
    • 2
  • Om Silakari
    • 1
  1. 1.Molecular Modeling Lab, Department of Pharmaceutical Sciences and Drug ResearchPunjabi UniversityPatialaIndia
  2. 2.Department of ChemistryPunjabi UniversityPatialaIndia

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