Skip to main content
Log in

Synthesis of novel benzothieno-[3,2’-f][1,3] oxazepines and their isomeric 2-oxo-2H-spiro[benzothiophene-3,3’-pyrrolines] via 1,4-dipolar cycloaddition reaction and their evaluation as cytotoxic anticancer leads

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


This study introduces a novel class of hybrid compounds, namely, benzothieno[3,2’-f][1,3]oxazepines and their isomeric 2-oxo-2H-spiro[benzothiophene-3,3’-pyrrolines]. The synthetic strategy employs a three-component reaction and 1,4-Dipolar cycloaddition, yielding spiro and oxazepine compounds. Structural elucidation via NMR and MS analyses is complemented by X-ray crystallography and a proposed mechanistic pathway. Biological evaluation against HEK-293 and HT-29 cells reveals potent and selective cytotoxicity against HEK-293 without cytotoxic effects against HT-29 cells. Compound 16c exhibited the highest cytotoxic properties with IC50 = 4.30 μM against HEK-293 cells. Accordingly, the new compounds can be considered as promising leads for possible optimization into novel selective cytotoxic treatments.

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

Access this article

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

Instant access to the full article PDF.

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

Similar content being viewed by others


  1. Al-Mahadeen MM, Zahra JA, El-Abadelah MM, Jaber AM, Khanfar MA. One-pot synthesis of novel 2-oxo (2H)-spiro [benzofuran-3, 3′-pyrrolines] via 1, 4-dipolar cycloaddition reaction. Res Chem. 2022;4:100643.

  2. Jaber AM, Zahra JA, El-Abadelah MM, Sabri SS, Sabbah DAS. Thermodynamic control synthesis of spiro[oxindole-3,3′-pyrrolines] via 1,4-dipolar cycloaddition utilizing imidazo[1,5-a]quinoline. Z Naturforsch C J Biosci. 2023;78:141–8.

  3. Zahedifar M, Pouramiri B, Ezzati Ghadi F, Razavi R, Ramzani Ghara A. Unexpected regio-and stereoselective [4 + 3] cycloaddition reaction of azomethine ylides with benzylidene thiazolidinediones: synthesis of pharmacologically active spiroindoline oxazepine derivatives and theoretical study. Mol Div. 2021;25:29–43.

    Article  CAS  Google Scholar 

  4. Mahmoud MA, Abed AY, Al-Nuzal SM. Synthesis and anticancer evaluation of new heterocyclic Compounds in cell line L20B in-vitro. J Pharm Sci. 2019;11:901–4.

    CAS  Google Scholar 

  5. Chen H, Liu H, Zhao S-H, Cheng S-B, Xu X-Y, Yuan W-C, et al. Enantioselective arylation of 3-carboxamide oxindoles with quinone monoimines and synthesis of chiral spirooxindole-benzofuranones. Synlett. 2019;30:1067–72.

    Article  CAS  Google Scholar 

  6. Gui HZ, Meng Z, Xiao ZS, Yang ZR, Wei Y, Shi M, Stereo‐and regioselective construction of spirooxindoles having continuous spiral rings via asymmetric [3 + 2] cyclization of 3‐isothiocyanato oxindoles with thioaurone derivatives. Eur J Organic Chem. 2020;2020:6614–22.

  7. Rana R, Ansari A. Synthesis of 7-membered heterocyclic compounds and their biological activity. J Physics: Conference Series. 2023. IOP Publishing

  8. Naruka YS, Eo A. Antimicrobial activity and characterization of seven synthetic formamidine disulfide derivatives. Innov J Sci. 2016;4:1–3.

    Google Scholar 

  9. Jaber AM, Zahra JA, El-Abadelah MM, Sabri SS, Sabbah D. Thermodynamic control synthesis of spiro [oxindole-3, 3′-pyrrolines] via 1, 4-dipolar cycloaddition utilizing imidazo [1, 5-a] quinoline. Z Naturforsch C J Biosci. 2023;78:141–8.

  10. Hiesinger K, Dar’in D, Proschak E, Krasavin M. Spirocyclic scaffolds in medicinal chemistry. J Med Chem. 2020;64:150–83.

    Article  PubMed  Google Scholar 

  11. Dabhi RA, Dhaduk MP, Bhatt VD, Bhatt BS. Synthetic approach toward spiro quinoxaline-β-lactam based heterocyclic compounds: Spectral characterization, SAR, pharmacokinetic and biomolecular interaction studies. J Biomol Struct Dyn. 2023;41:5382–98.

    Article  CAS  PubMed  Google Scholar 

  12. Bora D, Kaushal A, Shankaraiah N. Anticancer potential of spirocompounds in medicinal chemistry: A pentennial expedition. Eur J Med Chem. 2021;215:113263.

    Article  CAS  PubMed  Google Scholar 

  13. Mhiri C, Boudriga S, Askri M, Knorr M, Sriram D, Yogeeswari P, et al. Design of novel dispirooxindolopyrrolidine and dispirooxindolopyrrolothiazole derivatives as potential antitubercular agents. Bioorg Med Chem Lett. 2015;25:4308–13.

    Article  CAS  PubMed  Google Scholar 

  14. Jaber AM, Zahra JA, Sabri SS, Khanfar MA, Awwadi FF, El-Abadelah MM. New Trends in 1, 4-Dipolar Cycloaddition Reactions. Thermodynamic Control Synthesis of Model 2’-(isoquinolin-1-yl)-spiro [oxindole-3, 3’-pyrrolines]. Curr Org Chem. 2022;26:542–9.

  15. Jaber AM, Zahra JA, El-Abadelah MM, Sabri SS, Khanfar MA, Voelter W. Utilization of 1-phenylimidazo [1, 5-a] quinoline as partner in 1, 4-dipolar cycloaddition reactions. Z. Naturforsch. 2020;75:259–67.

    Article  CAS  Google Scholar 

  16. Sammor M, Hussein A, Awwadi F, El-abadelah M. One-pot synthesis of novel 3,10-dihydro-2 H -1,3-oxazepino[7,6- b]indoles via 1,4-dipolar cycloaddition reaction. Tetrahedron. 2017;74:42–48..

  17. Wang Q, Zhang S, Guo F, Zhang B, Hu P, Wang Z. Natural α-amino acids applied in the synthesis of imidazo [1, 5-a] N-heterocycles under mild conditions. J. Org. Chem. 2012;77:11161–6.

    Article  CAS  PubMed  Google Scholar 

  18. Yohda M, Yamamoto Y. Ruthenium–Me-BIPAM-catalyzed addition reaction of aryl-boronic acids to benzofuran-2,3-diones for the enantioselective synthesis of 3-aryl-3-hydroxybenzofuran-2-ones. Tetrahedron: Asymmetry. 2015;26:1430–5.

    Article  CAS  Google Scholar 

  19. Kropp KG, Goncalves JA, Andersson JT, Fedorak PM. Bacterial transformations of benzothiophene and methylbenzothiophenes. Environ Sci Technol. 1994;28:1348–56.

    Article  CAS  PubMed  Google Scholar 

  20. Sheldrick, GJAC, Sect. A, XS. version 2013/1, Georg-August-Universität Göttingen, Germany, 2013; b) GM Sheldrick. 71: 3-8. (2015).

  21. Sheldrick, GJJAC, SHELXTL V6. 1 Software Reference Manual, Bruker AXS Inc., Madison, WI, 2000 Search PubMed;(b) OV Dolomanov, LJ Bourhis, RJ Gildea, JAK Howard and H. Puschmann. 42: 339-41.(2009).

  22. Farrugia, LJJAC, ORTEP 3 for Windows, Version 1.0. 1β, University of Glasgow, 1997; LJ Farrugia. 30: 565. (1997).

  23. Wawszczyk J, Jesse K, Smolik S, Kapral M. Mechanism of Pterostilbene-Induced Cell Death in HT-29 Colon Cancer Cells. Molecules. 2022;27:369.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Jaber, AM; Al-Mahadeen, MM; Al-Qawasmeh, RA; Taha, M, Synthesis, anticancer evaluation and docking studies of novel adamantanyl-1, 3, 4-oxadiazol hybrid compounds as Aurora-A kinase inhibitors. Med Chem Res. 1-11. (2023).

Download references


We would like to thank the Deanship of Scientific Research at the University of Jordan, Amman-Jordan, for financial support.

Author information

Authors and Affiliations


Corresponding authors

Correspondence to Areej M. Jaber or Mutasem O. Taha.

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

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Al-Mahadeen, M.M., Jaber, A.M., Zahra, J.A. et al. Synthesis of novel benzothieno-[3,2’-f][1,3] oxazepines and their isomeric 2-oxo-2H-spiro[benzothiophene-3,3’-pyrrolines] via 1,4-dipolar cycloaddition reaction and their evaluation as cytotoxic anticancer leads. Med Chem Res (2024).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: