Skip to main content

Advertisement

SpringerLink
Log in

Synthesis and evaluation of novel arylisoxazoles linked to tacrine moiety: in vitro and in vivo biological activities against Alzheimer’s disease

  • Original Article
  • Published:
Molecular Diversity Aims and scope Submit manuscript

Abstract

Alzheimer’s disease (AD) is now ranked as the third leading cause of death after heart disease and cancer. There is no definite cure for AD due to the multi-factorial nature of the disease, hence, multi-target-directed ligands (MTDLs) have attracted lots of attention. In this work, focusing on the efficient cholinesterase inhibitory activity of tacrine, design and synthesis of novel arylisoxazole-tacrine analogues was developed. In vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition assay confirmed high potency of the title compounds. Among them, compounds 7l and 7b demonstrated high activity toward AChE and BChE with IC50 values of 0.050 and 0.039 μM, respectively. Both compounds showed very good self-induced Aβ aggregation and AChE-induced inhibitory activity (79.4 and 71.4% for compound 7l and 61.8 and 58.6% for compound 7b, respectively). Also, 7l showed good anti-BACE1 activity with IC50 value of 1.65 µM. The metal chelation test indicated the ability of compounds 7l and 7b to chelate biometals (Zn2+, Cu2+, and Fe2+). However, they showed no significant neuroprotectivity against Aβ-induced damage in PC12 cells. Evaluation of in vitro hepatotoxicity revealed comparable toxicity of compounds 7l and 7b with tacrine. In vivo studies by Morris water maze (MWM) task demonstrated that compound 7l significantly reversed scopolamine-induced memory deficit in rats. Finally, molecular docking studies of compounds 7l and 7b confirmed establishment of desired interactions with the AChE, BChE, and BACE1 active sites.

Graphic Abstract

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Scheme 1
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11

Similar content being viewed by others

References

  1. Patterson C (2018) World Alzheimer Report 2018—The State of the Art of Dementia Research: New Frontiers. Alzheimer’s Disease International (ADI), London

  2. Deture MA, Dickson DW (2019) The neuropathological diagnosis of Alzheimer’s disease. Mol Neurodegener 5:1–18. https://doi.org/10.1186/s13024-019-0333-5

    Article  Google Scholar 

  3. https://alz-journals.onlinelibrary.wiley.com/doi/full/https://doi.org/10.1002/alz.12068

  4. Piton M, Hirtz C, Desmetz C, Milhau J, Dominique-Lajoix A, Bennys K, Lehmann S, Gabelle A (2018) Alzheimer’s disease: advances in drug development. J Alzheimers Dis 65(1):3–13. https://doi.org/10.3233/JAD-180145

    Article  PubMed  Google Scholar 

  5. Oxford AE, Stewart ES, Rohn TT (2020) Clinical trials in Alzheimer's disease: A hurdle in the path of remedy. Int J Alzheimers Dis e5380346. https://doi.org/10.1155/2020/5380346.

  6. Dos-Santos-Picanco LC, Ozela PF, de-Fatima-de-Brito M, Pinheiro AA, Padilha EC, Braga FS, de-Paula-da-Silva CHT, Dos-Santos CBR, Rosa JMC, da-Silva-Hage-Melim LI (2018) Alzheimer's disease: A review from the pathophysiology to diagnosis, new perspectives for pharmacological treatment. Curr Med Chem 25(26):3141-3159. https://doi.org/10.2174/0929867323666161213101126

  7. Tobor TO (2019) On the etiopathogenesis and pathophysiology of Alzheimer’s disease: a comprehensive theoretical review. J Alzheimer’s Dis 68(2):417–437. https://doi.org/10.3233/JAD-181052

    Article  Google Scholar 

  8. Teipel SJ, Fritz HC, Grothe MJ (2020) Alzheimer's disease neuroimaging initiative. Neuropathologic features associated with basal forebrain atrophy in Alzheimer disease. Neurology 95(10):1301–1311. https://doi.org/10.1212/WNL.0000000000010192.

  9. Colautti J, Nagales K (2020) Tau and beta-amyloid in Alzheimer’s disease: Theories, treatments strategies, and future directions. Meducator 1(37):12–15. https://doi.org/10.15173/m.v1i37.2502

  10. Castellani RJ, Plascencia-Villa G, Perry G (2019) The amyloid cascade and Alzheimer’s disease therapeutics: theory versus observation. Lab Invest 99:958–970. https://doi.org/10.1038/s41374-019-0231-z

    Article  PubMed  Google Scholar 

  11. Moussa-Pacha NM, Abdin SM, Omar HA, Alniss H, Al-Tel TH (2020) BACE1 inhibitors: current status and future directions in treating Alzheimer’s disease. Med Res Rev 40:339–384. https://doi.org/10.1002/med.21622

    Article  PubMed  Google Scholar 

  12. Bruni AC, Bernardi L, Gabelli C (2020) From beta amyloid to altered proteostasis in Alzheimer’s disease. Ageing Res Rev. https://doi.org/10.1016/j.arr.2020.101126

    Article  PubMed  Google Scholar 

  13. Cacabelos R (2020) Pharmacogenetic considerations when prescribing cholinesterase inhibitors for the treatment of Alzheimer’s disease. Expert Opin Drug Metab Toxicol 16(8):673–701. https://doi.org/10.1080/17425255.2020.1779700

    Article  CAS  PubMed  Google Scholar 

  14. Whitehouse PJ, Price DL, Struble RG, Clark AW, Coyle JT, Delon MR (1982) Alzheimer’s disease and senile dementia: loss of neurons in the basal forebrain. Science 215(4537):1237–1239. https://doi.org/10.1126/science.7058341

    Article  CAS  PubMed  Google Scholar 

  15. Agatonovic-Kustrin S, Kettle C, Morton DW (2018) A molecular approach in drug development for Alzheimer’s disease. Biomed Pharmacother 106:553–565. https://doi.org/10.1016/j.biopha.2018.06.147

    Article  CAS  PubMed  Google Scholar 

  16. Sharma K (2019) Cholinesterase inhibitors as Alzheimer’s therapeutics (Review). Mol Med Rep 20(2):1479–1487. https://doi.org/10.3892/mmr.2019.10374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kabir MT, Uddin MS, Begum MM, Thangapandiyan S, Rahman MS, Aleya L, Mathew B, Ahmed M, Barreto GE, Ashraf GM (2019) Cholinesterase inhibitors for Alzheimer’s disease: multitargeting strategy based on anti-Alzheimer’s drugs repositioning. Curr Pharm Des 25(33):3519–3535. https://doi.org/10.2174/1381612825666191008103141

    Article  CAS  PubMed  Google Scholar 

  18. Martinez A, Castro A (2006) Novel cholinesterase inhibitors as future effective drugs for the treatment of Alzheimer’s disease. Expert Opin Invest Drugs 15(1):1–12. https://doi.org/10.1517/13543784.15.1.1

    Article  CAS  Google Scholar 

  19. Ismaili L, Refouvelet B, Benchekroun M, Brogi S, Brindisi M, Gemma S, Campiani G, Filipic S, Agbaba D, Esteban G, Unzeta M, Nikolic K, Butini S, Marco-Contelles J (2017) Multitarget compounds bearing tacrine-and donepezil-like structural and functional motifs for the potential treatment of Alzheimer’s disease. Prog Neurobiol 151:4–34. https://doi.org/10.1016/j.pneurobio.2015.12.003

    Article  CAS  PubMed  Google Scholar 

  20. McEneny-King A, Osman W, Edginton AN, Rao PPN (2017) Cytochrome P450 binding studies of novel tacrine derivatives: predicting the risk of hepatotoxicity. Bioorg Med Chem Lett 27(11):2443–2449. https://doi.org/10.1016/j.bmcl.2017.04.006

    Article  CAS  PubMed  Google Scholar 

  21. Sameem B, Saeedi M, Mahdavi M, Shafiee A (2017) A review on tacrine-based scaffolds as multi-target drugs (MTDLs) for Alzheimer’s disease. Eur J Med Chem 128:332–345. https://doi.org/10.1016/j.ejmech.2016.10.060

    Article  CAS  PubMed  Google Scholar 

  22. Riazimontazer E, Sadeghpour H, Nadri H, Sakhteman A, Tüylü Küçükkılınç T, Miri R, Edraki N (2019) Design, synthesis and biological activity of novel tacrine-isatin Schiff base hybrid derivatives. Bioorg Chem 89:103006. https://doi.org/10.1016/j.bioorg.2019.103006

    Article  CAS  PubMed  Google Scholar 

  23. Makhaeva GF, Kovaleva NV, Boltneva NP, Lushchekina SV, Rudakova EV, Stupina TS, Terentiev AA, Serkov IV, Proshin AN, Radchenko EV, Palyulin VA, Bachurin SO, Richardson RJ (2020) Conjugates of tacrine and 1,2,4-thiadiazole derivatives as new potential multifunctional agents for Alzheimer’s disease treatment: synthesis, quantum-chemical characterization, molecular docking, and biological evaluation. Bioorg Chem 94:103387. https://doi.org/10.1016/j.bioorg.2019.103387

    Article  CAS  PubMed  Google Scholar 

  24. Korabecny J, Musilek K, Zemek F, Horova A, Holas O, Nepovimova E, Opletalova V, Hroudova J, Fisar Z, Jung YS, Kuca K (2011) Synthesis and in vitro evaluation of 7-methoxy-N-(pent-4-enyl)-1,2,3,4-tetrahydroacridin-9-amine-new tacrine derivate with cholinergic properties. Bioorg Med Chem Lett 21:6563–6566. https://doi.org/10.1016/j.bmcl.2011.08.042

    Article  CAS  PubMed  Google Scholar 

  25. Pan T, Xie S, Zhou Y, Hu J, Luo H, Li X, Huang L (2019) Dual functional cholinesterase and PDE4D inhibitors for the treatment of Alzheimer’s disease: design, synthesis and evaluation of tacrine-pyrazolo[3,4-b]pyridine hybrids. Bioorg Med Chem Lett 29(16):2150–2152. https://doi.org/10.1016/j.bmcl.2019.06.056

    Article  CAS  PubMed  Google Scholar 

  26. Najafi Z, Mahdavi M, Mahdavi M, Saeedi M, Karimpour-Razkenari E, Asatouri R, Vafadarnejad F, Homayouni-Moghadam F, Khanavi M, Sharifzadeh M, Akbarzadeh T (2017) Novel tacrine-1,2,3-triazole hybrids: In vitro, in vivo biological evaluation and docking study of cholinesterase inhibitors. Eur J Med Chem 125:1200–1212. https://doi.org/10.1016/j.ejmech.2016.11.008

    Article  CAS  PubMed  Google Scholar 

  27. Hu MK, Lu CF (2000) A facile synthesis of bis-tacrine isosteres. Tetrahedron Lett 41(11):1815–1818. https://doi.org/10.1016/S0040-4039(00)00036-8

    Article  CAS  Google Scholar 

  28. Najafi Z, Mahdavi M, Saeedi M, Karimpour-Razkenari E, Edraki N, Sharifzadeh M, Khanavi M, Akbarzadeh T (2019) Novel tacrine-coumarin hybrids linked to 1,2,3-triazole as anti-Alzheimer’s compounds: In vitro and in vivo biological evaluation and docking study. Bioorg Chem 83:303–316. https://doi.org/10.1016/j.bioorg.2018.10.056

    Article  CAS  PubMed  Google Scholar 

  29. Saeedi M, Rastegari A, Hariri R, Mirfazli SS, Mahdavi M, Edraki N, Firuzi O, Akbarzadeh T (2020) Design and synthesis of novel arylisoxazole-chromenone carboxamides: investigation of biological activities associated with Alzheimer’s disease. Chem Biodivers 17(5):e1900746. https://doi.org/10.1002/cbdv.201900746

    Article  CAS  PubMed  Google Scholar 

  30. Vafadarnejad F, Mahdavi M, Karimpour-Razkenari E, Edraki N, Sameem B, Khanavi M, Saeedi M, Akbarzadeh T (2018) Design and synthesis of novel coumarin-pyridinium hybrids: In vitro cholinesterase inhibitory activity. Bioorg Chem 77:311–319. https://doi.org/10.1016/j.bioorg.2018.01.013

    Article  CAS  PubMed  Google Scholar 

  31. Najafi Z, Mahdavi M, Saeedi M, Sabourian R, Khanavi M, Safavi M, Tehrani MB, Shafiee A, Foroumadi A, Akbarzadeh T (2017) 1,2,3-Triazole-Isoxazole based acetylcholinesterase inhibitors: synthesis, biological evaluation and docking Study. Lett Drug Des Discov 14:58–65. https://doi.org/10.2174/1570180813666160628085515

    Article  CAS  Google Scholar 

  32. Saeedi M, Safavi M, Allahabadi E, Rastegari A, Hariri R, Jafari S, Bukhari SNA, Mirfazli SS, Firuzi O, Edraki N, Mahdavi M, Akbarzadeh T (2020) Thieno[2,3-b]pyridine amines: synthesis and evaluation of tacrine analogs against biological activities related to Alzheimer’s disease. Arch Pharm 353:e2000101. https://doi.org/10.1002/ardp.202000101

    Article  CAS  Google Scholar 

  33. Karimi-Askarani H, Iraji A, Rastegari A, Abbas-Bukhari SN, Firuzi O, Akbarzadeh T, Saeedi M (2020) Design and synthesis of multi-target directed 1,2,3-triazole-dimethylaminoacryloyl-chromenone derivatives with potential use in Alzheimer's disease. BMC Chem 14(1):pe64. https://doi.org/10.1186/s13065-020-00715-0.

  34. Iraji A, Firuzi O, Khoshneviszadeh M, Tavakkoli M, Mahdavi M, Nadri H, Edraki N, Miri R (2017) Multifunctional iminochromene-2H-carboxamide derivatives containing different aminomethylene triazole with BACE1 inhibitory, neuroprotective and metal chelating properties targeting Alzheimer’s disease. Eur J Med Chem 141:690–702. https://doi.org/10.1016/j.ejmech.2017.09.057

    Article  CAS  PubMed  Google Scholar 

  35. Iraji A, Firuzi O, Khoshneviszadeh M, Nadri H, Edraki N, Miri R (2018) Synthesis and structure-activity relationship study of multi-target triazine derivatives as innovative candidates for treatment of Alzheimer’s disease. Bioorg Chem 77:223–235. https://doi.org/10.1016/j.bioorg.2018.01.017

    Article  CAS  PubMed  Google Scholar 

  36. Edraki N, Firuzi O, Fatahi Y, Mahdavi M, Asadi M, Emami S, Divsalar K, Miri R, Iraji A, Khoshneviszadeh M, Firoozpour L, Shafiee A, Foroumadi A (2015) N-(2-(Piperazin-1-yl)phenyl)arylamide derivatives as β-secretase (BACE1) inhibitors: simple synthesis by Ugi Four-component reaction and biological evaluation. Arch Pharm 348(5):330–337. https://doi.org/10.1002/ardp.201400322

    Article  CAS  Google Scholar 

  37. Martorana A, Giacalone V, Bonsignore R, Pace A, Gentile C, Pibiri I, Buscemi S, Lauria A, Piccionello AP (2016) Heterocyclic scaffolds for the treatment of Alzheimer’s disease. Curr Pharm Des 22:3971–3995

    Article  CAS  Google Scholar 

  38. Saeedi M, Mohtadi-Haghighi D, Mirfazli SS, Mahdavi M, Hariri R, Lotfian H, Edraki N, Iraji A, Firuzi O, Akbarzadeh T (2019) Design and synthesis of selective acetylcholinesterase inhibitors: Arylisoxazole-Phenylpiperazine derivatives. Chem Biodivers 16:e1800433. https://doi.org/10.1002/cbdv.201800433

    Article  CAS  PubMed  Google Scholar 

  39. Vafadarnejad F, Saeedi M, Mahdavi M, Rafinejad A, Karimpour-Razkenari E, Sameem B, Khanavi M, Akbarzadeh T (2017) Novel indole-isoxazole hybrids: synthesis and in vitro anti-cholinesterase activity. Lett Drug Des Discov 14:712–717. https://doi.org/10.2174/1570180813666161018124726

    Article  CAS  Google Scholar 

  40. Vafadarnejad F, Karimpour-Razkenari E, Sameem B, Saeedi M, Firuzi O, Edraki N, Mahdavi M, Akbarzadeh T (2019) Novel N-benzylpyridinium moiety linked to arylisoxazole derivatives as selective butyrylcholinesterase inhibitors: Synthesis, biological evaluation, and docking study. Bioorg Chem 92:103192. https://doi.org/10.1016/j.bioorg.2019.103192

    Article  CAS  PubMed  Google Scholar 

  41. Ragab HM, Teleb M, Haidar HR, Gouda N (2019) Chlorinated tacrine analogs: Design, synthesis and biological evaluation of their anti-cholinesterase activity as potential treatment for Alzheimer’s disease. Bioorg Chem 86:557–568. https://doi.org/10.1016/j.bioorg.2019.02.033

    Article  CAS  PubMed  Google Scholar 

  42. Ragab HM, Ashour HMA, Galal A, Ghoneim AI, Haidar HR (2016) Synthesis and biological evaluation of some tacrine analogs: study of the effect of the chloro substituent on the acetylcholinesterase inhibitory activity. Monatsh Chem 147:539–552. https://doi.org/10.1007/s00706-015-1641-2

    Article  CAS  Google Scholar 

  43. Keri RS, Quintanova C, Chaves S, Silva DF, Cardoso SM, Santos MA (2016) New tacrine hybrids with natural-based cysteine derivatives as multitargeted drugs for potential treatment of Alzheimer’s disease. Chem Biol Drug Des 87(1):101–111. https://doi.org/10.1111/cbdd.12633

    Article  CAS  PubMed  Google Scholar 

  44. Wilcken R, Zimmermann MO, Lange A, Joerger AC, Boeckler FM (2013) Principles and applications of halogen bonding in medicinal chemistry and chemical biology. J Med Chem 56(4):1363–1388. https://doi.org/10.1021/jm3012068

    Article  CAS  PubMed  Google Scholar 

  45. Iraji A, Khoshneviszadeh M, Firuzi O, Khoshneviszadeh M, Edraki N (2020) Novel small molecule therapeutic agents for Alzheimer disease: Focusing on BACE1 and multi-target directed ligands. Bioorg Chem 97:e103649. https://doi.org/10.1016/j.bioorg.2020.103649

    Article  CAS  Google Scholar 

  46. Yazdani M, Edraki N, Badri R, Khoshneviszadeh M, Iraji A, Firuzi O (2020) 5,6-Diphenyl triazine-thio methyl triazole hybrid as a new Alzheimer’s disease modifying agents. Mol Divers 24:641–654. https://doi.org/10.1007/s11030-019-09970-3

    Article  CAS  PubMed  Google Scholar 

  47. Liao J, Nai Y, Feng L, Chen Y, Li M, Xu H (2020) Walnut oil prevents scopolamine-induced memory dysfunction in a mouse model. Molecules 25:pe1630. https://doi.org/10.3390/molecules25071630.

  48. Vorhees CV, Williams MT (2006) Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 1:848–858. https://doi.org/10.1038/nprot.2006.116

    Article  PubMed  PubMed Central  Google Scholar 

  49. Brandeis R, Brandys Y, Yehuda S (1989) The use of the Morris Water Maze in the study of memory and learning. Int J Neurosci 48(1–2):29–69. https://doi.org/10.3109/00207458909002151

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Research Council of Tehran University of Medical Sciences with project No. 98-01-33-41955.

Author information

Authors and Affiliations

  1. Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, Tehran, Iran

    Arezoo Rastegari, Mina Saeedi & Tahmineh Akbarzadeh

  2. Department of Biotechnology, Iranian Research Organization for Science and Technology (IROST), Tehran, Iran

    Maliheh Safavi

  3. Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

    Fahimeh Vafadarnejad, Roshanak Hariri & Tahmineh Akbarzadeh

  4. Department of Medicinal Chemistry, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran

    Zahra Najafi

  5. Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Aljouf, 2014, Sakaka, Saudi Arabia

    Syed Nasir Abbas Bukhari

  6. Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

    Aida Iraji

  7. Central Research laboratory, Shiraz University of Medical Sciences, Shiraz, Iran

    Aida Iraji

  8. Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

    Najmeh Edraki & Omidreza Firuzi

  9. Medicinal Plants Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

    Mina Saeedi

  10. Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran

    Mohammad Mahdavi

Authors
  1. Arezoo Rastegari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maliheh Safavi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fahimeh Vafadarnejad
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zahra Najafi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Roshanak Hariri
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Syed Nasir Abbas Bukhari
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Aida Iraji
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Najmeh Edraki
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Omidreza Firuzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mina Saeedi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Mohammad Mahdavi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Tahmineh Akbarzadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tahmineh Akbarzadeh.

Ethics declarations

Conflict of interest

The authors declare that there is no conflict of financial or personal interests that could have appeared to influence the content of this paper.

Additional information

Publisher's Note

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

This paper is dedicated to our unique teacher in chemistry and medicinal chemistry (1937-2016)

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 8319 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rastegari, A., Safavi, M., Vafadarnejad, F. et al. Synthesis and evaluation of novel arylisoxazoles linked to tacrine moiety: in vitro and in vivo biological activities against Alzheimer’s disease. Mol Divers 26, 409–428 (2022). https://doi.org/10.1007/s11030-021-10248-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11030-021-10248-w

Keywords

Search

Navigation