Skip to main content
SpringerLink
Log in

Synthesis, in vitro, and in silico studies of newly functionalized quinazolinone analogs for the identification of potent α-glucosidase inhibitors

  • Original Paper
  • Published:
Journal of the Iranian Chemical Society Aims and scope Submit manuscript

Abstract

Functionalized quinazolinone derivatives 1–30 were synthesized by two-step reaction. First, anthranilic acid was treated with substituted phenyl isothiocyanate to synthesize 3-aryl-2-thioxo-2,3-dihydroquinazolinone derivatives 1–8 which in turn reacted with different bromoacetophenone derivatives to obtain fully functionalized quinazolinone derivatives 9–30. Both reactions were catalyzed by triethylamine. All the products were characterized by EI-, HREI-MS, 1H-, and 13CNMR spectroscopic techniques. All compounds were subjected to their in vitro α-glucosidase inhibitory activity. Results showed that except compound 1–3, 5, 7, and 22, all compounds were found potent and showed many folds increased α-glucosidase enzyme inhibition as compared to standard acarbose (IC50 = 750.0 ± 10.0 µM). Compound 13 (IC50 = 85.0 ± 0.5 µM) was recognized as the most potent analog of the whole series, with ninefold enhanced inhibitory potential than the standard acarbose. Compounds 1–9, 11, 12, 22, and 26 were structurally known compounds, while remaining all are new. Kinetic study on compound 13 showed that the compound is following a competitive-type inhibition mechanism. Furthermore, in silico studies have also been performed to better rationalize the interactions between synthetic compound and active site of the enzyme.

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

Similar content being viewed by others

References

  1. S. Ibrahim, A. Al-Ahdal, A. Khedr, G. Mohamed, Rev. Bras. Farmacogn. 27, 170 (2017)

    Article  CAS  Google Scholar 

  2. J.C. Burani, L. Rao, Good Carbs, Bad Carbs: An Indispensable Guide to Eating the Right Carbs for Losing Weight and Optimum Health. Marlowe and Company, 2002.

  3. M. Ajaib, S. Fatima, S.H. Kamran, K.M. Khan, S. Perveen, S. Shah, J. Chem. Soc. Pak. 38, 1267 (2016)

    CAS  Google Scholar 

  4. M. Ajaib, M. Latif, S.H. Kamran, K.M. Khan, S. Perveen, S. Shah, A. Karim, J. Chem. Soc. Pak. 38, 313 (2016)

    CAS  Google Scholar 

  5. M.A. Abbasi, S.A.H. Shah, Aziz-ur-Rehman, S.Z. Siddiqui, G. Hussain, K.M. Khan, M. Ashraf, S.A. Ejaz, J. Chem. Soc. Pak. 39, 248 (2017).

  6. H. King, M. Rewers, Diabetes Care 16, 57 (1993)

    Article  Google Scholar 

  7. P.R. Flanagan, G.G. Forstner, Biochem. J. 173, 553 (1978)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. S. Chiba, Bioscience, Biotechnol. Biochem. 61, 1233 (1997)

    CAS  Google Scholar 

  9. K.T. Kim, L.E. Rioux, S.L. Turgeon, Phytochemistry 9, 827 (2014)

    Google Scholar 

  10. A.R. Saltiel, C.R. Kahn, Nature 414, 799 (2001)

    Article  CAS  PubMed  Google Scholar 

  11. H. Sun, D. Wang, X. Song, Y. Zhang, W. Ding, X. Peng, X. Zhang, Y. Li, Y. Ma, R. Wang, J. Agric Food Chem. 65, 1574 (2017)

    Article  CAS  PubMed  Google Scholar 

  12. P.M. Heacock, S.R. Hertzler, J.A. Williams, B.W. Wolf, J. Am. Diet. Assoc. 105, 65 (2005)

    Article  PubMed  Google Scholar 

  13. S.D. Kim, Food Chem. 136, 297 (2013)

    Article  CAS  PubMed  Google Scholar 

  14. N. Jong-Anurakkun, M.R. Bhandari, J. Kawabata, Food Chem. 103, 1319 (2007)

    Article  CAS  Google Scholar 

  15. J.J. DiNicolantonio, J. Bhutani, J.H. O’Keefe, Open Heart 2, 1 (2015)

    Google Scholar 

  16. M.A. Avery, C.S. Mizuno, A.G. Chittiboyina, T.W. Kurtz, H.A. Pershadsingh, Curr. Med. Chem. 15, 61 (2008)

    Article  PubMed  Google Scholar 

  17. B.R. Miller, H. Nguyen, C.J.H. Hu, C. Lin, Q.T. Nguyen, Am. Health Drug Benef. 7, 452 (2014)

    CAS  Google Scholar 

  18. A.D. Mooradian, J.E. Thurman, Drugs 57, 19 (1999)

    Article  CAS  PubMed  Google Scholar 

  19. M.M. Wang, G.L. Dou, D.Q. Shi, J. Heterocycl. Chem. 47, 939 (2010)

    Article  CAS  Google Scholar 

  20. O.O. Ajani, Bangladesh. J. Pharmacol. 11, 716 (2016)

    Google Scholar 

  21. I. Monreal, M. Sánchez-Castellanos, K. Ramírez-Gualito, G. Cuevas, K.A. Espinoza, I.A. Rivero, J. Braz. Chem. Soc. 30, 124 (2019)

    CAS  Google Scholar 

  22. M. Asif, Int. J. Med. Chem. 2014, 1 (2014)

    Google Scholar 

  23. S.K. Pandey, A. Singh, A. Singh, Eur. J. Med. Chem. 44, 1188 (2009)

    Article  CAS  PubMed  Google Scholar 

  24. M.A. Mohamed, R.R. Ayyad, T.Z. Shawer, A.-M. Alaa, A.S. El-Azab, Eur. J. Med. Chem. 112, 106 (2016)

    Article  CAS  PubMed  Google Scholar 

  25. S. Allameh, M. Heravi, M. Hashemi, F. Bamoharram, Chin. Chem. Lett. 22, 131 (2011)

    Article  CAS  Google Scholar 

  26. N.M.A. Gawad, H.H. Georgey, R.M. Youssef, N.A. El Sayed, Med. Chem. Res. 20, 1280 (2011)

    Article  Google Scholar 

  27. G. Moussa, R. Alaaeddine, L.M. Alaeddine, R. Nassra, A.S. Belal, A. Ismail, A.F. El-Yazbi, Y.S. Abdel-Ghany, A. Hazzaa, Eur. J. Med. Chem. 144, 635 (2018)

    Article  CAS  PubMed  Google Scholar 

  28. F.M. Refaie, A.Y. Esmat, S.M.A. Gawad, A.M. Ibrahim, M.A. Mohamed, Lipids Health Dis. 4, 22 (2005)

    Article  PubMed  PubMed Central  Google Scholar 

  29. Y.I. El-Gazzar, H.H. Georgey, S.M. El-Messery, H.A. Ewida, G.S. Hassan, M.M. Raafat, M.A. Ewida, H.I. El-Subbagh, Bioorg. Chem. 72, 282 (2017)

    Article  CAS  PubMed  Google Scholar 

  30. M. Redondo, J.G. Zarruk, P. Ceballos, D.I. Pérez, C. Pérez, A. Perez-Castillo, M.A. Moro, J. Brea, C. Val, M.I. Cadavid, Eur. J. Med. Chem. 47, 175 (2012)

    Article  CAS  PubMed  Google Scholar 

  31. S.T. Al-Rashood, G.S. Hassan, S.M. El-Messery, M.N. Nagi, E.S.E. Habib, F.A. Al-Omary, H.I. El-Subbagh, Bioorg. Med. Chem. Lett. 24, 4557 (2014)

    Article  CAS  PubMed  Google Scholar 

  32. G.G. Berest, O.Y. Voskoboynik, S.I. Kovalenko, O.M. Antypenko, I.S. Nosulenko, A.M. Katsev, O.S. Shandrovskaya, Eur. J. Med. Chem. 46, 6066 (2011)

    Article  CAS  PubMed  Google Scholar 

  33. M.L. Heil, N.D. Cosford, R. Ardecky, and J. Zou, Google Patents, U.S. Patent No. 9,598,402. Washington, DC: U.S. Patent and Trademark Office (2017).

  34. Y. Kabri, N. Azas, A. Dumetre, S. Hutter, M. Laget, P. Verhaeghe, A. Gellis, P. Vanelle, Eur. J. Med. Chem. 45, 616 (2010)

    Article  CAS  PubMed  Google Scholar 

  35. H. Niaz, H. Kashtoh, J.A. Khan, A. Khan, M.T. Alam, K.M. Khan, S. Perveen, M.I. Choudhary, Eur. J. Med. Chem. 95, 199 (2015)

    Article  CAS  PubMed  Google Scholar 

  36. U. Salar, M. Taha, K.M. Khan, N.H. Ismail, S. Imran, S. Perveen, S. Gul, A. Wadood, Eur. J. Med. Chem. 122, 196 (2016)

    Article  CAS  PubMed  Google Scholar 

  37. K.M. Khan, F. Rahim, A. Wadood, N. Kosar, M. Taha, S. Lalani, A. Khan, M.I. Fakhri, M. Junaid, W. Rehman, Eur. J. Med. Chem. 81, 245 (2014)

    Article  CAS  PubMed  Google Scholar 

  38. F. Rahim, H. Ullah, M.T. Javid, A. Wadood, M. Taha, M. Ashraf, A. Shaukat, M. Junaid, S. Hussain, W. Rehman, Bioorg. Chem. 62, 15 (2015)

    Article  CAS  PubMed  Google Scholar 

  39. K. Javaid, S.M. Saad, S. Rasheed, S.T. Moin, N. Syed, I. Fatima, U. Salar, K.M. Khan, S. Perveen, M.I. Choudhary, Bioorg. Med. Chem. 23, 7417 (2015)

    Article  CAS  PubMed  Google Scholar 

  40. H. Kashtoh, S. Hussain, A. Khan, S.M. Saad, J.A. Khan, K.M. Khan, S. Perveen, M.I. Choudhary, Bioorg. Med. Chem. 22, 5454 (2014)

    Article  CAS  PubMed  Google Scholar 

  41. M. Taha, N.H. Ismail, S. Lalani, M.Q. Fatmi, S. Siddiqui, K.M. Khan, S. Imran, M.I. Choudhary, Eur. J. Med. Chem. 92, 387 (2015)

    Article  CAS  PubMed  Google Scholar 

  42. S. Hameed, F. Seraj, R. Rafique, S. Chigurupati, A. Wadood, A.U. Rehman, V. Venugopal, U. Salar, M. Taha, K.M. Khan, Eur. J. Med. Chem. 183, 1 (2019)

    Article  Google Scholar 

  43. M. Adib, F. Peytam, M. Rahmanian-Jazi, S. Mahernia, H.R. Bijanzadeh, M. Jahani, M. Mohammadi-Khanaposhtani, S. Imanparast, M.A. Faramarzi, M. Mahdavi, Eur. J. Med. Chem. 155, 353 (2018)

    Article  CAS  PubMed  Google Scholar 

  44. A.I. Khodair, M.A. Alsafi, M.S. Nafie, Carbohydr. Res. 486, 107832 (2019)

    Article  CAS  PubMed  Google Scholar 

  45. W. Liu, Q. Zhang, F. Gong, Z. Cao, Y. Huo, J. Heterocycl. Chem. 52, 317 (2015)

    Article  CAS  Google Scholar 

  46. H.X. Wang, H.Y. Liu, W. Li, S. Zhang, Z. Wu, X. Li, C.-W. Li, Y.M. Liu, B.Q. Chen, Med. Chem. Res. 28, 203 (2019)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors are thankful to the Pakistan Academy of Sciences, Pakistan, for providing financial support to Project No. (5-9/PAS/440).

Author information

Authors and Affiliations

  1. H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan

    Hayat Wali, Shahbaz Shamim & Khalid Mohammed Khan

  2. Department of Biological Sciences, School of Science and Technology, Sunway University, Subang Jaya, 47500, Selangor, Malaysia

    Ayaz Anwar

  3. Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam, 31441, Saudi Arabia

    Khalid Mohammed Khan & Muhammad Taha

  4. Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran

    Mohammad Mahdavi & Bagher Larijani

  5. Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan

    Uzma Salar

  6. PCSIR Laboratories Complex, Karachi, Shahrah-e-Dr. Salimuzzaman Siddiqui, Karachi, 75280, Pakistan

    Shahnaz Perveen

  7. Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

    Mohammad Ali Faramarzi

Authors
  1. Hayat Wali
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ayaz Anwar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shahbaz Shamim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Khalid Mohammed Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mohammad Mahdavi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Uzma Salar
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bagher Larijani
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shahnaz Perveen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Muhammad Taha
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mohammad Ali Faramarzi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Khalid Mohammed Khan.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file 1 (PDF 10481 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wali, H., Anwar, A., Shamim, S. et al. Synthesis, in vitro, and in silico studies of newly functionalized quinazolinone analogs for the identification of potent α-glucosidase inhibitors. J IRAN CHEM SOC 18, 2017–2034 (2021). https://doi.org/10.1007/s13738-021-02159-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13738-021-02159-2

Keywords

Search

Navigation