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image of Synthesis of New Calixarene Derivatives and Evaluation of their Acetylcholinesterase Inhibitory Activities

Abstract

Background

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, with current treatments focused on inhibiting acetylcholinesterase (AChE) to sustain acetylcholine levels in brain.

Objective

In this work, three new calixarene derivatives , , and were synthesized and evaluated against AChE and .

Methods

Firstly, target compounds , , and were synthesized from calix[4]arene (1), and after characterization, they were evaluated against AChE. The most potent compound, as determined by evaluation, underwent additional studies, including a docking study, pharmacokinetics analysis, and density functional theory (DFT) analysis.

Results

The most potent compound was the pyridin-2-yl-chalcone derivative , which interacted well with the active site of AChE. This compound also has an acceptable energy gap between HOMO and LUMO orbitals as a drug candidate. The pharmacokinetics and toxicity profiles of new calixarene derivatives 3, 5, and 7 were satisfactory.

Discussion

The results of this study demonstrate that the newly synthesized calixarene derivatives, particularly compound 7, exhibit promising activity against acetylcholinesterase (AChE), both and through analysis.

Conclusion

Our and results suggest that the calixarene derivatives are promising candidates for targeting AChE.

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2025-09-04
2026-01-31

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References

  1. Srivastava S. Ahmad R. Khare S.K. Alzheimer’s disease and its treatment by different approaches: A review. Eur. J. Med. Chem. 2021 216 113320 10.1016/j.ejmech.2021.113320 33652356
    [Google Scholar]
  2. Monzio Compagnoni G. Di Fonzo A. Corti S. Comi G.P. Bresolin N. Masliah E. The role of mitochondria in neurodegenerative diseases: The lesson from Alzheimer’s disease and Parkinson’s disease. Mol. Neurobiol. 2020 57 7 2959 2980 10.1007/s12035‑020‑01926‑1 32445085
    [Google Scholar]
  3. Oliyaei N. Moosavi-Nasab M. Tanideh N. Iraji A. Multiple roles of fucoxanthin and astaxanthin against Alzheimer’s disease: Their pharmacological potential and therapeutic insights. Brain Res. Bull. 2023 193 11 21 10.1016/j.brainresbull.2022.11.018 36435362
    [Google Scholar]
  4. Iraji A. Khoshneviszadeh M. Firuzi O. Khoshneviszadeh M. Edraki N. Novel small molecule therapeutic agents for Alzheimer disease: Focusing on BACE1 and multi-target directed ligands. Bioorg. Chem. 2020 97 103649 10.1016/j.bioorg.2020.103649 32101780
    [Google Scholar]
  5. Sharma K. Cholinesterase inhibitors as Alzheimer’s therapeutics.(Review). Mol. Med. Rep. 2019 20 2 1479 1487 10.3892/mmr.2019.10374 31257471
    [Google Scholar]
  6. Thawabteh A.M. Ghanem A.W. AbuMadi S. Thaher D. Jaghama W. Karaman D. Karaman R. Recent advances in therapeutics for the treatment of Alzheimer’s disease. Molecules 2024 29 21 5131 10.3390/molecules29215131 39519769
    [Google Scholar]
  7. Pan Y.C. Hu X.Y. Guo D.S. Biomedical applications of calixarenes: State of the art and perspectives. Angew. Chem. Int. Ed. 2021 60 6 2768 2794 10.1002/anie.201916380 31965674
    [Google Scholar]
  8. Andersson C.D. Forsgren N. Akfur C. Allgardsson A. Berg L. Engdahl C. Qian W. Ekström F. Linusson A. Divergent structure-activity relationships of structurally similar acetylcholinesterase inhibitors. J. Med. Chem. 2013 56 19 7615 7624 10.1021/jm400990p 23984975
    [Google Scholar]
  9. Gao J. Guo D-S. Supramolecular medicine of diverse calixarene derivatives. In: Handbook of Macrocyclic Supramolecular Assembly. Singapore Springer 2020 201 229 10.1007/978‑981‑15‑2686‑2_9
    [Google Scholar]
  10. de Fátima A. Fernandes S. Sabino A. Calixarenes as new platforms for drug design. Curr. Drug Discov. Technol. 2009 6 2 151 170 10.2174/157016309788488302 19519339
    [Google Scholar]
  11. Guo D.S. Liu Y. Supramolecular chemistry of p-sulfonatocalix[n]arenes and its biological applications. Acc. Chem. Res. 2014 47 7 1925 1934 10.1021/ar500009g 24666259
    [Google Scholar]
  12. Pidany F. Kroustkova J. Jenco J. Breiterova K.H. Muckova L. Novakova L. Kunes J. Fibigar J. Kucera T. Novak M. Sorf A. Hrabinova M. Pulkrabkova L. Janousek J. Soukup O. Jun D. Korabecny J. Cahlikova L. Carltonine-derived compounds for targeted butyrylcholinesterase inhibition. RSC Med. Chem. 2024 15 5 1601 1625 10.1039/D4MD00060A 38784455
    [Google Scholar]
  13. Stoikova E.E. Evtugyn G.A. Belyakova S.V. Khrustalev A.A. Stoikov I.I. Antipin I.S. Budnikov H.C. Konovalov A.I. 1,3-Disubstituted p-tert-Butylcalix[4]arenes as Cholinesterase Inhibitors. J. Incl. Phenom. Macrocycl. Chem. 2001 39 3/4 339 346 10.1023/A:1011109509185
    [Google Scholar]
  14. Padnya P.L. Bayarashov E.E. Zueva I.V. Lushchekina S.V. Lenina O.A. Evtugyn V.G. Osin Y.N. Petrov K.A. Stoikov I.I. Water-soluble betaines and amines based on thiacalix[4]arene scaffold as new cholinesterase inhibitors. Bioorg. Chem. 2020 94 103455 10.1016/j.bioorg.2019.103455 31791680
    [Google Scholar]
  15. Oguz M. Kalay E. Akocak S. Nocentini A. Lolak N. Boga M. Yilmaz M. Supuran C.T. Synthesis of calix[4]azacrown substituted sulphonamides with antioxidant, acetylcholinesterase, butyrylcholinesterase, tyrosinase and carbonic anhydrase inhibitory action. J. Enzyme Inhib. Med. Chem. 2020 35 1 1215 1223 10.1080/14756366.2020.1765166 32401067
    [Google Scholar]
  16. Lhoták P. Upper rim-bridged calixarenes. RSC Advances 2024 14 32 23303 23321 10.1039/D4RA04663C 39049889
    [Google Scholar]
  17. Ellman G.L. Courtney K.D. Andres V. Featherstone R.M. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharmacol. 1961 7 2 88 95 10.1016/0006‑2952(61)90145‑9 13726518
    [Google Scholar]
  18. Zareei S. Mohammadi-Khanaposhtani M. Shahali M. Şenol H. Badbedast M. Moazzam A. Mohseni S. Esfahani E.N. Ekti S.F. Larijani B. Mahdavi M. Ibrahim E.H. Ghramh H.A. Taslimi P. Phenyldiazenyl-phenoxy-1,2,3-triazol-acetamide derivatives as new dual cholinesterase Inhibitors: Design, synthesis, in vitro, and in silico enzymatic inhibition evaluations. J. Mol. Struct. 2025 1321 139686 10.1016/j.molstruc.2024.139686
    [Google Scholar]
  19. Zahedi N.A. Mohammadi-Khanaposhtani M. Rezaei P. Askarzadeh M. Alikhani M. Adib M. Mahdavi M. Larijani B. Niakan S. Tehrani M.B. Taslimi P. Gulçin I. Dual functional cholinesterase and carbonic anhydrase inhibitors for the treatment of Alzheimer’s disease: Design, synthesis, in vitro, and in silico evaluations of coumarin-dihydropyridine derivatives. J. Mol. Struct. 2023 1276 134767 10.1016/j.molstruc.2022.134767
    [Google Scholar]
  20. Pires D.E.V. Blundell T.L. Ascher D.B. pkCSM: Predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures. J. Med. Chem. 2015 58 9 4066 4072 10.1021/acs.jmedchem.5b00104 25860834
    [Google Scholar]
  21. Lee S.K. Kang Y. Chang G.S. Lee I.H. Park S.H. Park J. Welcome to the PreADMET. 2017 Available from https://preadmet.bmdrc.kr
    [Google Scholar]
  22. Liu H. Liu X. Fan H. Tang J. Gao X. Liu W.K. Design, synthesis and pharmacological evaluation of chalcone derivatives as acetylcholinesterase inhibitors. Bioorg. Med. Chem. 2014 22 21 6124 6133 10.1016/j.bmc.2014.08.033 25260958
    [Google Scholar]
  23. Bajda M. Więckowska A. Hebda M. Guzior N. Sotriffer C. Malawska B. Structure-based search for new inhibitors of cholinesterases. Int. J. Mol. Sci. 2013 14 3 5608 5632 10.3390/ijms14035608 23478436
    [Google Scholar]
  24. Guan H. Sun H. Zhao X. Application of density functional theory to molecular engineering of pharmaceutical formulations. Int. J. Mol. Sci. 2025 26 7 3262 10.3390/ijms26073262 40244098
    [Google Scholar]
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Synthesis of New Calixarene Derivatives and Evaluation of their Acetylcholinesterase Inhibitory Activities
Bentham Science Publishers ; https://doi.org/10.2174/0115701794415787251105112322
/content/journals/cos/10.2174/0115701794415787251105112322
/content/journals/cos/10.2174/0115701794415787251105112322
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  • Article Type:     Research Article
Keywords: DFT ; Calixarene ; acetylcholinesterase ; docking ; pharmacokinetics ; Alzheimer's disease

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