Skip to main content
SpringerLink
Log in

An Efficient One-pot Synthesis of Certain Stereoselective Spiro[pyrazole-4,5′-isoxazoline]-5-one Derivatives: In vitro Evaluation of Antitumor Activities, Molecular Docking and In silico ADME Predictions

  • Article
  • Published:
Chemical Research in Chinese Universities Aims and scope

Abstract

Alibrary of novel spiro[pyrazole-4,5′-isoxazoline]-5-one derivatives were designed and synthesized using a concise and efficient one-pot reaction protocol through 1,3-dipolar cycloaddition between 4-benzylidene-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one and chlorooximes. The synthesized derivatives were elucidated and characterized based on their spectroscopic data, including infrared spectrometry(IR), 1H NMR, 13C NMR, and elemental and mass spectral analysis. The synthesized compounds were evaluated for their antitumor inhibition potency against four human cancer cell lines, including human prostatic adenocarcinoma (PC3), human colorectal carcinoma(HCT116), human liver hepatocellular carcinoma(HepG2) and breast adenocarcinoma (MCF7). The outcomes were compared with the standard reference drug Doxorubicin. Among the synthesized chlorooximes, compounds 6d and 6e were the most active compounds on all cell lines. The spiro[pyrazole-4,5′-isoxazoline]-5-one derivatives 7a and 7c were active on the HepG2 liver cancer cell line. In comparison, compounds 7f and 7g were moderately active on the MCF7 cell line. The structure-activity relationship was explored for the synthesized compounds. Besides, in silico analysis of physicochemical, adsorption, distribution, metabolism, excretion and toxicity(ADMET) properties were done to determine the potential capacity of drug candidates. Molecular docking study onto the epidermal growth factor(EGF) tyrosine kinase receptor(3POZ) was done for the most active compounds to validate the reliability of in vitro anticancer screenings.

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

Similar content being viewed by others

References

  1. Chauhan A., Sharma P., Kaushik N., Int. J. ChemTech Res., 2011, 3(1), 11

    Google Scholar 

  2. Brogden R. N., Drugs, 1986, 32(4), 60

    Article  Google Scholar 

  3. Kasiotis K. M., Tzanetou E. N., Haroutounian S. A., Frontiers in Chemistry, 2014, 2, 78

    Article  Google Scholar 

  4. Kumar V., Kaur K., Gupta G. K., Sharma A. K., European Journal of Medicinal Chemistry, 2013, 69, 735

    Article  CAS  Google Scholar 

  5. Sondhi S. M., Jain S., Dinodia M., Shukla R., Raghubir R., Bioorganic & Medicinal Chemistry, 2007, 15(10), 3334

    Article  CAS  Google Scholar 

  6. Palaska E., Aytemir M., Uzbay I. T., Erol D., European Journal of Medicinal Chemistry, 2001, 36(6), 539

    Article  CAS  Google Scholar 

  7. Ma R., Zhu J., Liu J., Chen L., Shen X., Jiang H., Li J., Molecules, 2010, 15(5), 3593

    Article  CAS  Google Scholar 

  8. Ribeiro C. J., Rodrigues C. M., Moreira R., Santos M. M., Pharmaceuticals, 2016, 9(2), 25

    Article  Google Scholar 

  9. Khazir J., Singh P. P., Reddy D. M., Hyder I., Shafi S., Sawant S., Chashoo G., Mahajan A., Alam M., Saxena A., European Journal of Medicinal Chemistry, 2013, 63, 279

    Article  CAS  Google Scholar 

  10. Das P., Boone S., Mitra D., Turner L., Tandon R., Raucher D., Hamme A. T., RSC Advances, 2020, 10(50), 30223

    Article  CAS  Google Scholar 

  11. Karale B., Gadhave A., Indian Journal of Heterocyclic Chemistry, 2010, 19(4), 389

    CAS  Google Scholar 

  12. Duffy J. L., Bao J., Ondeyka D. L., Tyagarajan S., Shao P., Ye F., Katipally R., Finke P. E., Zang Y., Plotkin M. A., Patent WO 2011/146324, 2011

  13. Zhang P.-Z., Li X.-L., Chen H., Li Y.-N., Wang R., Tetrahedron Letters, 2007, 48(44), 7813

    Article  CAS  Google Scholar 

  14. Zhu S., Shi S., Gerritz S. W., Tetrahedron Letters, 2011, 52(31), 4001

    Article  CAS  Google Scholar 

  15. Singh R., Goff D., Partridge J. J., Substituted diphenyl isoxazoles, pyrazoles and oxadiazoles useful for treating HCV infection, Patent US-2004266840-A1, 2006

  16. Hassner A., Synthesis of Heterocycles via Cycloadditions I, Vol. 12, Springer, Verlag Berlin Heidelberg, 2008

    Book  Google Scholar 

  17. Namboothiri I., Rastogi N., Springer, Berlin, Germany, 2008, 1

  18. Sammelson R. E., Gurusinghe C. D., Kurth J. M., Olmstead M. M., Kurth M. J., Journal of Organic Chemistry, 2002, 67(3), 876

    Article  CAS  Google Scholar 

  19. Yazdani H., Bazgir A., Synthesis, 2019, 51(07), 1669

    Article  CAS  Google Scholar 

  20. Masumoto E., Shirouzu E., Kashige N., Okabe-Nakahara F., Miake F., Yamagata K., Maruoka H., Heterocycles, 2018, 96(7), 1289

    Article  CAS  Google Scholar 

  21. Outahar F., Moumou M., Hannioui A., Rakib E. M., El Ammari L., Saadi M., Akssira M., Tetrahedron Letters, 2020, 61(42), 152409

    Article  CAS  Google Scholar 

  22. Bora D., Kaushal A., Shankaraiah N., European Journal of Medicinal Chemistry, 2021, 113263

  23. Madhuswapnaja K. J., Yennam S., Chavali M., Chemistry of Biologically Potent Natural Products and Synthetic Compounds, 2021, 155

  24. Yu S., Qin D., Shangary S., Chen J., Wang G., Ding K., McEachern D., Qiu S., Nikolovska-Coleska Z., Miller R., Journal of Medicinal Chemistry, 2009, 52(24), 7970

    Article  CAS  Google Scholar 

  25. Ewies E. F., El-Hussieny M., El-Sayed N. F., Ali M. M., Mahmoud A. E., Phosphorus, Sulfur, and Silicon and the Related Elements, 2016, 191 (7), 1000

    Article  CAS  Google Scholar 

  26. Boulos L. S., Ewies E. F., Fahmy A. F., Mohram M. E., Phosphorus, Sulfur, and Silicon and the Related Elements, 2013, 188(6), 790

    Article  CAS  Google Scholar 

  27. Ibrahim N. M., Yosef H. A., Ewies E. F., Mahran M. R., Ali M. M., Mahmoud A. E., Journal of the Brazilian Chemical Society, 2015, 26(6), 1086

    CAS  Google Scholar 

  28. Ewies E. F., El-Shehry M. F., Boulos L. S., Int. J. ChemTech Res., 2015, 7, 2506

    CAS  Google Scholar 

  29. Cohen J. B., A Class-book of Organic Chemistry, Vol.1, Macmillan and Co., Limited, London, 1920

    Google Scholar 

  30. Jiang K. M., Zhang J. Q., Jin Y., Lin J., Asian J. Org. Chem., 2017, 6, 1620

    Article  CAS  Google Scholar 

  31. Franke A., Justus Liebigs Ann. Chem., 1978, 717

  32. Azizian J., Jadidi K., Mehrdad M., Sarrafi Y., Synth. Commun., 2000, 30, 2309

    Article  CAS  Google Scholar 

  33. Liu K.-C., Shelton B. R., Howe R. K., Journal of Organic Chemistry, 1980, 45(19), 3916

    Article  CAS  Google Scholar 

  34. Mosmann T., J. Immunological Methods, 1983, 65(1/2), 55

    Article  CAS  Google Scholar 

  35. Irmer D., Funk J., Blaukat A., Oncogene, 2007, 26(39), 5693

    Article  CAS  Google Scholar 

  36. Berasain C., Avila M. A., Journal of Gastroenterology, 2014, 49(1), 9

    Article  CAS  Google Scholar 

  37. Aertgeerts K., Skene R., Yano J., Sang B.-C., Zou H., Snell G., Jennings A., Iwamoto K., Habuka N., Hirokawa A., Journal of Biological Chemistry, 2011, 286(21), 18756

    Article  CAS  Google Scholar 

  38. Risitano F., Grassi G., Foti F., Heterocycles, 2003, 60(4), 857

    Article  CAS  Google Scholar 

  39. Ribeiro C. J., Amaral J. D., Rodrigues C. M., Moreira R., Santos M. M., Bioorganic & Medicinal chemistry, 2014, 22(1), 577

    Article  CAS  Google Scholar 

  40. Phillips A. M. F., Pombeiro A. J., Kopylovich M. N., ChemCatChem, 2017, 9(2), 217

    Article  Google Scholar 

  41. Wheeldon I., Minteer S. D., Banta S., Barton S. C., Atanassov P., Sigman M., Nature Chemistry, 2016, 8(4), 299

    Article  CAS  Google Scholar 

  42. Zhao M. Y., Abraham M. H., Le J., Hersey A., Luscombe C. N., Beck G., Sherborne B., Cooper I., Pharm. Res., 2002, 19, 1446

    Article  CAS  Google Scholar 

  43. Veber D. F., Johnson S. R., Cheng H.-Y., Smith B. R., Ward K. W., Kopple K. D., Journal of Medicinal Chemistry, 2002, 45(12), 2615

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Fund of National Research Centre, Egypt.

Author information

Authors and Affiliations

  1. Chemistry Department, College of Science, Taibah University, P. O. Box 30002, Code 14177, Al-Madinah Al Munawarah, Saudi Arabia

    Ghadah F. Aljohani

  2. Department of Chemistry of Natural and Microbial Products, National Research Centre, Dokki, P. O. Box 12622, Giza, Egypt

    Fatma A. A. El-Hag

  3. Pesticide Chemistry Department, National Research Centre, Dokki, P. O. Box 12622, Giza, Egypt

    Mohamed S. Bekheit

  4. Organometallic and Organometalloid Chemistry Department, National Research Centre, Dokki, P. O. Box 12622, Giza, Egypt

    Ewies F. Ewies

  5. Department of Pharmacognosy, National Research Centre, Dokki, P. O. Box 12622, Giza, Egypt

    May A. El-Manawaty

Authors
  1. Ghadah F. Aljohani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fatma A. A. El-Hag
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mohamed S. Bekheit
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ewies F. Ewies
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. May A. El-Manawaty
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Ghadah F. Aljohani or Fatma A. A. El-Hag.

Additional information

Conflicts of Interest

The authors declare no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Aljohani, G.F., El-Hag, F.A.A., Bekheit, M.S. et al. An Efficient One-pot Synthesis of Certain Stereoselective Spiro[pyrazole-4,5′-isoxazoline]-5-one Derivatives: In vitro Evaluation of Antitumor Activities, Molecular Docking and In silico ADME Predictions. Chem. Res. Chin. Univ. 38, 1073–1082 (2022). https://doi.org/10.1007/s40242-022-1408-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40242-022-1408-3

Keywords

Search

Navigation