Skip to main content
SpringerLink
Log in

Synthesis of 1,2,3-benzotriazin-4(3H)-one derivatives as α-glucosidase inhibitor and their in-silico study

  • Original Research
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

Abstract

α-Glucosidase inhibition is considered as an effective strategy for the treatment of diabetes mellitus. Currently, three α-glucosidase inhibitors are being used as drugs; Acarbose, Voglibose and Miglitol. The side effects of these drugs are forcing researchers to search for new and effective molecules. In this research work, novel 1,2,3-benzotriazin-4(3H)-one sulfonamides were synthesized and investigated for their α-glucosidase inhibition activity. 2,4,6-Trichloro-1,3,5-triazine: N,N-dimethylformamide (TCT : DMF) adduct have been utilized for the direct synthesis of targeted sulfonamides. All reactions were performed at room temperature under mild conditions. In-vitro enzyme inhibition studies led us to discover many potent inhibitors demonstrating good to excellent activity. The compound 5c with dimethyl substituent was found to be a more potent inhibitor than acarbose with the IC50 value of 29.75 ± 0.14 μM. Compounds 5a, 5b, 5d, 5e, 5f, and 5m showed good inhibition results with IC50 value 31.97 ± 0.03, 33.24 ± 0.01, 33.76 ± 1.05, 35.98 ± 0.03, 30.87 ± 0.51, and 37.24 ± 0.04 µM respectively. Further structure activity relationship was analyzed by molecular docking studies.

Graphical abstract

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

Access this article

Log in via an institution

We’re sorry, something doesn't seem to be working properly.

Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

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

Similar content being viewed by others

References

  1. Taha M, Alrashedy AS, Almandil NB, Iqbal N, Nawaz M, Uddin N, et al. Synthesis of indole derivatives as diabetics II inhibitors and enzymatic kinetics study of α-glucosidase and α-amylase along with their in-silico study. Int J Biol Macromol. 2021;190:301–18. https://doi.org/10.1016/j.ijbiomac.2021.08.207

    Article  CAS  PubMed  Google Scholar 

  2. Alomari M, Taha M, Rahim F, Selvaraj M, Iqbal N, Chigurupati S, et al. Synthesis of indole-based-thiadiazole derivatives as a potent inhibitor of α-glucosidase enzyme along with in silico study. Bioorg Chem. 2021;108:104638 https://doi.org/10.1016/j.bioorg.2021.104638

    Article  CAS  PubMed  Google Scholar 

  3. Seo WD, Kim JH, Kang JE, Ryu HW, Curtis-Long MJ, Lee HS, et al. Sulfonamide chalcone as a new class of α-glucosidase inhibitors. Bioorg Med Chem Lett. 2005;15:5514–6. https://doi.org/10.1016/j.bmcl.2005.08.087

    Article  CAS  PubMed  Google Scholar 

  4. Kausar N, Ullah S, Khan MA, Zafar H, Choudhary MI, Yousuf S. Celebrex derivatives: synthesis, α-glucosidase inhibition, crystal structures and molecular docking studies. Bioorg Chem. 2021;106:104499 https://doi.org/10.1016/j.bioorg.2020.104499

    Article  CAS  PubMed  Google Scholar 

  5. Akocak S, Taslimi P, Lolak N, Işık M, Durgun M, Budak Y, et al. Synthesis, Characterization, and Inhibition Study of Novel Substituted Phenylureido Sulfaguanidine Derivatives as α‐Glycosidase and Cholinesterase Inhibitors. Chem Biodivers. 2021;18:e2000958 https://doi.org/10.1002/cbdv.202000958

    Article  CAS  PubMed  Google Scholar 

  6. Devaraj S, Yip YM, Panda P, Ong LL, Wong PWK, Zhang D, et al. Cinnamoyl Sucrose Esters as Alpha Glucosidase Inhibitors for the Treatment of Diabetes. Molecules 2021;26:469 https://doi.org/10.3390/molecules26020469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Elgemeie GH, Azzam RA, Elsayed RE. Sulfa drug analogs: new classes of N-sulfonyl aminated azines and their biological and preclinical importance in medicinal chemistry (2000–2018). Med Chem Res. 2019;28:1099–131. https://doi.org/10.1007/s00044-019-02378-6

    Article  CAS  Google Scholar 

  8. Mukherjee P, Woroch CP, Cleary L, Rusznak M, Franzese RW, Reese MR, et al. Sulfonamide synthesis via calcium triflimide activation of sulfonyl fluorides. Org Lett. 2018;20:3943–7. https://doi.org/10.1021/acs.orglett.8b01520

    Article  CAS  PubMed  Google Scholar 

  9. Khalid Z, Ahmad HA, Munawar MA, Khan M-U-A, Gul S. 1, 2, 3-Benzotriazin-4 (3H)-ones: synthesis, reactions and applications. Heterocycles 2017;94:3–54. https://doi.org/10.3987/REV-16-846

    Article  CAS  Google Scholar 

  10. Fiorino F, Magli E, Perissutti E, Severino B, Frecentese F, Esposito A, et al. Synthesis of 1-naphtylpiperazine derivatives as serotoninergic ligands and their evaluation as antiproliferative agents. Eur J Med Chem. 2011;46:2206–16. https://doi.org/10.1016/j.ejmech.2011.03.001

    Article  CAS  PubMed  Google Scholar 

  11. Ibrahim TS, Rashad AA, Abdel-Samii ZK, El-Feky SA, Abdel-Hamid MK. Barakat W. Synthesis, molecular modeling and anti-inflammatory screening of new 1, 2, 3-benzotriazinone derivatives. Med Chem Res. 2012;21:4369–80. https://doi.org/10.1007/s00044-012-9975-3

    Article  CAS  Google Scholar 

  12. Raffa D, Migliara O, Maggio B, Plescia F, Cascioferro S, Cusimano MG, et al. Pyrazolobenzotriazinone Derivatives as COX Inhibitors: Synthesis, Biological Activity, and Molecular‐Modeling Studies. Arch Pharm. 2010;343:631–8. https://doi.org/10.1002/ardp.200900317

    Article  CAS  Google Scholar 

  13. Fiorino F, Severino B, De Angelis F, Perissutti E, Frecentese F, Massarelli P, et al. Synthesis and In‐vitro Pharmacological Evaluation of New 5‐HT1A Receptor Ligands Containing a Benzotriazinone Nucleus. Arch Pharm. 2008;341:20–7. https://doi.org/10.1002/ardp.200700151

    Article  CAS  Google Scholar 

  14. Raffa D, Daidone G, Maggio B, Schillaci D. Plescia F. Synthesis and Antiproliferative Activity of Novel 3‐(Indazol‐3‐yl)‐quinazolin‐4 (3H)‐one and 3‐(Indazol‐3‐yl)‐benzotriazin‐4 (3H)‐one Derivatives. Arch Pharm. 1999;332:317–20. https://doi.org/10.1002/(SICI)1521-4184(19999)332:9%3C317::AID-ARDP317%3E3.0.CO;2-R

    Article  CAS  Google Scholar 

  15. Fiorino F, Caliendo G, Perissutti E, Severino B, Frecentese F, Preziosi B, et al. Synthesis by microwave irradiation and antidiarrhoeal activity of benzotriazinone and saccharine derivatives. J Org Chem. 2005;338:548–55. https://doi.org/10.1002/ardp.200500134

    Article  CAS  Google Scholar 

  16. Caliendo G, Fiorino F, Grieco P, Perissutti E, Santagada V, Meli R, et al. Preparation and local anaesthetic activity of benzotriazinone and benzoyltriazole derivatives. Eur J Med Chem. 1999;34:1043–51. https://doi.org/10.1016/S0223-5234(99)00126-9

    Article  CAS  Google Scholar 

  17. Reddy GS, Snehalatha AV, Edwin RK, Hossain KA, Giliyaru VB, Hariharapura RC, et al. Synthesis of 3-indolylmethyl substituted (pyrazolo/benzo) triazinone derivatives under Pd/Cu-catalysis: Identification of potent inhibitors of chorismate mutase (CM). Bioorg Chem. 2019;91:103155 https://doi.org/10.1016/j.bioorg.2019.103155

    Article  CAS  PubMed  Google Scholar 

  18. El Rayes S, Ali I, Fathalla W, Mahmoud M. Synthesis and Biological Activities of Some New Benzotriazinone Derivatives Based on Molecular Docking; Promising HepG2 Liver Carcinoma Inhibitors. ACS Omega. 2020;5:6781–91. https://doi.org/10.1021/acsomega.0c00116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ahmad HA, Gillani SS, Babar R, Munawar MA, Gulb S. A Rapid and Efficient Protocol for the Synthesis of Cinnamils. INEOS OPEN. 2020;3:20–4. https://doi.org/10.32931/io2002a

    Article  CAS  Google Scholar 

  20. Chaudhry F, Shahid W, al-Rashida M, Ashraf M, Ali Munawar M, Ain Khan M. Synthesis of imidazole-pyrazole conjugates bearing aryl spacer and exploring their enzyme inhibition potentials. Bioorg Chem. 2021;108:104686 https://doi.org/10.1016/j.bioorg.2021.104686

    Article  CAS  PubMed  Google Scholar 

  21. Ahmad HA, Aslam M, Gul S, Mehmood T, Munawar MA. In vivo Anti Inflammation Studies of Novel 1, 2, 5 Oxadiazole Sulfonamide Hybrids. Pak J Zool. 2021. https://doi.org/10.17582/journal.pjz/20200601040658

    Article  Google Scholar 

  22. De Luca L, Giacomelli G. An easy microwave-assisted synthesis of sulfonamides directly from sulfonic acids. J Org Chem. 2008;73:3967–9. https://doi.org/10.1021/jo800424g

    Article  CAS  PubMed  Google Scholar 

  23. Caddick S, Wilden J, Bush H, Wadman S, Judd D. A new route to sulfonamides via intermolecular radical addition to pentafluorophenyl vinylsulfonate and subsequent aminolysis. Org Lett. 2002;4:2549–51. https://doi.org/10.1021/ol026181m

    Article  CAS  PubMed  Google Scholar 

  24. Shaabani A, Soleimani E, Rezayan AH. A novel approach for the synthesis of alkyl and aryl sulfonamides. Tetrahedron Lett. 2007;48:2185–8. https://doi.org/10.1016/j.tetlet.2007.01.091

    Article  CAS  Google Scholar 

  25. Clark R, Wagner E. Isatoic anhydride. I. Reactions with primary and secondary amines and with some amides1. J Org Chem. 1944;9:55–67. https://doi.org/10.1021/jo01183a007

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors acknowledge the School of Chemistry, University of the Punjab Lahore, Pakistan for providing us chemicals and instrumental facilities.

Author information

Authors and Affiliations

  1. Department of Chemistry, Kinnaird College for Women, Lahore, Pakistan

    Zunera Khalid

  2. School of Chemistry, University of the Punjab, Lahore, Pakistan

    Zunera Khalid, Hafiz A. Ahmad & Munawar A. Munawar

  3. Department of Chemistry, University of Education, Township, Lahore, Pakistan

    Syed S. Shafqat

  4. School of Biochemistry and Biotechnology, University of the Punjab, Lahore, Pakistan

    Hafiz M. Rehman

  5. Department of Chemistry, University of the Central Punjab, Lahore, Pakistan

    Munawar A. Munawar

  6. Department of Chemistry, Government College University, Faisalabad, Pakistan

    Matloob Ahmad

  7. Department of Chemistry, King Abdul Aziz University, Jeddah, Saudi Arabia

    Abdullah M. Asiri

  8. Department of Biochemistry and Biotechnology, The Islamia University of Bahawalpur, Bahawalpur, Pakistan

    Muhammad Ashraf

Authors
  1. Zunera Khalid
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Syed S. Shafqat
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hafiz A. Ahmad
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hafiz M. Rehman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Munawar A. Munawar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Matloob Ahmad
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Abdullah M. Asiri
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Muhammad Ashraf
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Hafiz A. Ahmad or Munawar A. Munawar.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

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

Supplementary Information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Khalid, Z., Shafqat, S.S., Ahmad, H.A. et al. Synthesis of 1,2,3-benzotriazin-4(3H)-one derivatives as α-glucosidase inhibitor and their in-silico study. Med Chem Res 31, 819–831 (2022). https://doi.org/10.1007/s00044-022-02883-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-022-02883-1

Keywords

Search

Navigation