10.57647/pibm.2023.122315

Synthesis, in Silico Pharmaceutical Properties, Anticancer and Anti-Inflammatory Activities of Novel Benzo[b]thiophene Derivative

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  • Shayesteh Poorhosein Ghazi Mahaleh*1,
  • Muheb. A. S. Algso2,
  • Omruye Ozok Arici3,
  • Arif Kivrak4,
  • Sevki Arslan1,
  1. Department of Biology, Faculty of Science, Pamukkale University, Denizli 20160, Turkey
  2. Department of Chemistry, College of Science, University of Duhok, Duhok 42001, Iraq
  3. Biomedical Engineering, Faculty of Engineering and Architectural Science, Eskisehir Osmangazi University, Eskisehir 26040, Turkey
  4. Department of Chemistry, Faculty of Science, Eskisehir Osmangazi University, Eskisehir 26040, Turkey
Synthesis, in Silico pharmaceutical properties, anticancer and antiinflamatory activities of novel Benzo[b]thiophene derivative

Received: 2023-08-21

Revised: 2023-09-23

Accepted: 2023-09-28

Published in Issue 2023-09-30

Copyright (c) 2025 Copyright © 2024, The Author(s), under exclusive licence to Islamic Azad University

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

How to Cite

Poorhosein Ghazi Mahaleh, S., Algso, M. A. S., Ozok Arici, O., Kivrak, A., & Arslan, S. (2023). Synthesis, in Silico Pharmaceutical Properties, Anticancer and Anti-Inflammatory Activities of Novel Benzo[b]thiophene Derivative. Progress in Biomaterials, 12(3). https://doi.org/10.57647/pibm.2023.122315
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Abstract

Sulfur-containing compounds have various biological functions, the most important of which are anti-inflammatory and anticancer effects. This study provides the first evaluation of the biological potential of a novel benzothiophene derivative, 3-iodo-2-phenylbenzo[b]thiophene (IPBT), with a special focus on its cytotoxic, anticancer, cell migration, colony formation and anti-inflammatory properties. The EC50 values ​​of IPBT were determined in MDA-MB-231, HepG2, LNCaP, Caco-2, Panc-1, HeLa and Ishikawa cancer cell lines (126.67, 67.04, 127.59, 63.74, 76.72, 146.75 and 110.84 respectively). The compound was found to induce apoptosis by activating the expression levels of pro-apoptotic genes (BAX, CASP3, CASP8, CASP9, and P53) in cancer cells and effectively inhibit cell migration and colony formation. IPBT also significantly reduced inflammatory responses (Nitric oxide production) in LPS-induced RAW264.7 macrophage cells by proinflammatory genes (COX-2, iNOS, TNF-α, and IL-6). These findings suggest that IPBT may be a promising candidate for cancer treatment as well as a therapeutic agent for controlling inflammation and tissue repair.

Keywords

  • In silico synthesis,
  • Anticancer activity,
  • Anti-inflammatory,
  • Benzo[b]thiophene
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References

  1. Hiremath, C.G., Heggnnavar, G.B., Kariduraganavar, M.Y., Hiremath, M.B.: Co-delivery of paclitaxel and curcumin to folate-positive cancer cells using Pluronic-coated iron oxide nanoparticles. Prog. Biomater. 8, 155–168 (2019). https://doi.org/10.1007/s40204-019-0118-5
  2. Ma, X., Yu, H.: Global burden of cancer. Yale J. Biol. Med. 79(3-4), 85–94 (2007).
  3. Sung, H., Ferlay, J., Siegel, R.L., Laversanne, M., Soerjomataram, I., Jemal, A., Bray, F.: Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71(3), 209–249 (2021). https://doi.org/10.3322/caac.21660
  4. Cao, W., Chen, H.-D., Yu, Y.-W., Li, N., Chen, W.-Q.: Changing profiles of cancer burden worldwide and in China: a secondary analysis of the global cancer statistics 2020. Chin. Med. J. 134(7), 783–791 (2021). https://doi.org/10.1097/CM9.0000000000001474
  5. Haberkorn, U.: What is cancer? In Advances in Nuclear Oncology, 1st ed.; CRC Press, Boca Raton, FL, USA, pp. 1–16 (2007). https://doi.org/10.3109/9781420091380-5
  6. Hanahan, H., Weinberg, R.A.: Hallmarks of cancer: the next generation. Cell 144(5), 646–674 (2011). https://doi.org/10.1016/j.cell.2011.02.013
  7. Pedraza-Fariña, L.G.: Mechanisms of oncogenic cooperation in cancer initiation and metastasis. Yale J. Biol. Med. 79(3-4), 95–103 (2007).
  8. Hegde, P.S., Chen, D.S.: Top 10 challenges in cancer immunotherapy. Immunity 52(1), 17–35, 2020. https://doi.org/10.1016/j.immuni.2019.12.011
  9. Zhao, H., Wu, L., Yan, G., Chen, Y., Zhou, M., Wu, Y., Li, Y.: Inflammation and tumor progression: signaling pathways and targeted intervention. Signal Transduct. Target. Ther. 6, 263 (2021). https://doi.org/10.1038/s41392-021-00658-5
  10. Debela, D.T., Muzazu, S.G.Y., Manyazewal, T.: New approaches and procedures for cancer treatment: current perspectives. SAGE Open Med. 9, 20503121211034366 (2021). https://doi.org/10.1177/20503121211034366
  11. Q. Nie., Y. Hu., X. Yu., X. Li., X. Fang: Induction and application of ferroptosis in cancer therapy, Cancer Cell Int. 22:12 (2022). 10.1186/s12935-021-02366-0
  12. Pucci, C., Martinelli, G., Ciofani, G.: Innovative approaches for cancer treatment: current perspectives and new challenges. Ecancermedicalscience 13, 961 (2019). https://doi.org/10.3332/ecancer.2019.961
  13. Kalaria, P.N., Karad, S.C., Raval, D.K.: A review on diverse heterocyclic compounds as the privileged scaffolds in antimalarial drug discovery. Eur. J. Med. Chem. 158, 917–936 (2018). https://doi.org/10.1016/j.ejmech.2018.08.040
  14. T. Qadir., A. Amin., P.K. Sharma., I. Jeelani., H. Abe.: A review on medicinally important heterocyclic compounds, Open Med. Chem. J. 16: e2202280 (2022). 10.2174/18741045-v16-e2202280
  15. Mishra, R., Kumar, N., Mishra, I., Sachan, N.: A review on anticancer activities of thiophene and its analogs. Mini Rev. Med. Chem. 20(19), 1944–1965 (2020). https://doi.org/10.2174/1389557520666200715104555
  16. B. Rosada., A. Bekier., J. Cytarska., W. Płaziński., O. Zavyalova., A. Sikora., K. Dzitko., K.Z Łączkowski.: Benzo[b]thiophene-thiazoles as potent anti-Toxoplasma gondii agents: Design, synthesis, tyrosinase/tyrosine hydroxylase inhibitors, molecular docking study, and antioxidant activity, Eur. J. Med. Chem. 184:111765 (2019). https://doi.org/10.1016/j.ejmech.2019.111765
  17. Fakhr, I.M.I., Radwan, M.A.A., El-Batran, S., Abd El-Salam, O.M.E., El-Shenawy, S.M.: Synthesis and pharmacological evaluation of 2-substituted benzo[b]thiophenes as anti-inflammatory and analgesic agents. Eur. J. Med. Chem. 44(4), 1718–1725 (2009). https://doi.org/10.1016/j.ejmech.2008.02.034
  18. A. Singh., G. Singh., P.M.S. Bedi.: Thiophene derivatives: A potent multitargeted pharmacological scaffold, J. Heterocycl. Chem. 57(7):2658–2703 (2020). 10.1002/jhet.3990
  19. Shah, R., Verma, P.K.: Synthesis of thiophene derivatives and their anti-microbial, antioxidant, anticorrosion and anticancer activity. BMC Chem. 13, 54 (2019). https://doi.org/10.1186/s13065-019-0569-8
  20. Haridevamuthu, B., Manjunathan, T., Guru, A., Kumar, R.S., Rajagopal, R., Kuppusamy, P., Juliet, A., Gopinath, P., Arockiaraj, J.: Hydroxyl containing benzo[b]thiophene analogs mitigates the acrylamide induced oxidative stress in the zebrafish larvae by stabilizing the glutathione redox cycle. Life Sci. 298, 120507 (2022). https://doi.org/10.1016/j.lfs.2022.120507
  21. Mabkhot, Y.N., Kaal, N.A., Alterary, S., Mubarak, M.S., Alsayari, A., Muhsinah, A.B.: New thiophene derivatives as antimicrobial agents. J. Heterocycl. Chem. 56(10), 2845–2953 (2019). https://doi.org/10.1002/jhet.3688
  22. Archna, A., Pathania, S., Chawla, P.A.: Thiophene-based derivatives as anticancer agents: an overview on decade’s work. Bioorg. Chem. 101, 104026 (2020). https://doi.org/10.1016/j.bioorg.2020.104026
  23. Gad, E.M., Nafie, M.S., Eltamany, E.H., Hammad, M.S.A.G., Barakat, A., Boraei, A.T.A.: Discovery of new apoptosis-inducing agents for breast cancer based on ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate: synthesis, in vitro, and in vivo activity evaluation. Molecules 25(11), 2523 (2020). https://doi.org/10.3390/molecules25112523
  24. Deng, Q., Gu, J., Zhang, H., Zhang, Y., Meng, X.: Sustainable access to benzothiophene derivatives bearing a trifluoromethyl group via a three-component domino reaction in water. Org. Biomol. Chem. 2022, 20, 6611–6619. https://doi.org/10.1039/D2OB01034H
  25. Keri, R.S., Chand, K., Budagumpi, S., Somappa, S.B., Patil, S.A., Nagaraja, B.M.: An overview of benzo[b]thiophene-based medicinal chemistry. Eur. J. Med. Chem. 138, 1002–1033 (2017). https://doi.org/10.1016/j.ejmech.2017.07.038
  26. de Vasconcelos, A., Campos, V.F., Nedel, F., Seixas, F.K., Dellagostin, O.A., Smith, K.R., Pereira de Pereira, C.M.: Cytotoxic and apoptotic effects of chalcone derivatives of 2-acetyl thiophene on human colon adenocarcinoma cells. Cell Biochem. Funct. 31(4), 289–297 (2013). https://doi.org/10.1002/cbf.2897
  27. Zarei, O., Azimian, F., Hamzeh-Mivehroud, M., Shahbazi Mojarrad, J., Hemmati, S., Dastmalchi, S.: Design, synthesis, and biological evaluation of novel benzo[b]thiophene-diaryl urea derivatives as potential anticancer agents. Med. Chem. Res. 29, 1438–1448 (2020). https://doi.org/10.1007/s00044-020-02559-8
  28. El-Metwally, S.A., Khalil, A.K., El-Naggar, A.M., El-Sayed, W.M.: Novel Tetrahydrobenzo[b] Thiophene Compounds Exhibit Anticancer Activity through Enhancing Apoptosis and Inhibiting Tyrosine Kinase, Anti-Cancer Agents Med. Chem. 18(12):1761–1769 (2018). 10.2174/1871520618666180813120558
  29. Kosmalski, T., Hetmann, A., Studzińska, R., Baumgart, S., Kupczyk, D., Roszek, K.: The oxime ethers with heterocyclic, alicyclic and aromatic moiety as potential anti-cancer agents. Molecules 2022, 27(4), 1374. https://doi.org/10.3390/molecules27041374
  30. Zhang, W., Ma, T., Li, S., Yang, Y., Guo, J., Yu, W., Kong, L.: Antagonizing STAT3 activation with benzo[b]thiophene 1,1-dioxide based small molecules. Eur. J. Med. Chem. 125, 538–550 (2017). https://doi.org/10.1016/j.ejmech.2016.09.068
  31. Xue, D., Chen, W., Neamati, N.: Discovery, structure-activity relationship study and biological evaluation of 2-thioureidothiophene-3-carboxylates as a novel class of C-X-C chemokine receptor 2 (CXCR2) antagonists. Eur. J. Med. Chem. 204, 112387 (2020). https://doi.org/10.1016/j.ejmech.2020.112387
  32. D. Caro., D. Rivera,, Y. Ocampo,, K. Müller,, L.A. Franco.: A promising naphthoquinone [8-hydroxy-2-(2-thienylcarbonyl)naphtho[2,3-b]thiophene-4,9-dione] exerts anti-colorectal cancer activity through ferroptosis and inhibition of MAPK signaling pathway based on RNA sequencing, Open Chem. 18:1242–1255 (2020). 10.1515/chem-2020-0170
  33. Rodrigues, J. R., Charris, J., Camacho, J., Barazarte, A., Gamboa, N., Nitzsche, B., Höpfner, M., Lein, M., Jung, K., Abramjuk, C.: N′-Formyl-2-(5-nitrothiophen-2-yl) benzothiazole-6-carbohydrazide as a potential anti-tumour agent for prostate cancer in experimental studies. J. Pharm. Pharmacol. 65(3), 411–422 (2013). https://doi.org/10.1111/j.2042-7158.2012.01607.x
  34. Romagnoli, R., Preti, D., Hamel, E., Bortolozzi, R., Viola, G., Brancale, A., Ferla, S., Morciano, G., Pinton, P.: Concise synthesis and biological evaluation of 2-aryl-3-anilinobenzo[b]thiophene derivatives as potent apoptosis-inducing agents. Bioorg. Chem. 112, 104919 (2021). https://doi.org/10.1016/j.bioorg.2021.104919
  35. Li, W.-Z., Xi, H.-Z., Wang, Y.-J., Ma, H.-B., Cheng, Z.-Q., Yang, Y., Wu, M.-L., Liu, T.-M., Yang, W., Wang, Q., Liao, M.-Y., Zhang, Y.-W., Xia, Y.: Design, synthesis, and biological evaluation of benzo[b]thiophene 1,1‐dioxide derivatives as potent STAT3 inhibitors. Chem. Biol. Drug Des. 98(5), 835–849 (2021). https://doi.org/10.1111/cbdd.13939
  36. Abd El-Rahman, S.A., Wafa, E.I., Ebeid, K., Geary, S.M., Naguib, Y.W., El-Damasy, A.K., Salem, A.K.: Thiophene derivative-loaded nanoparticles mediate anticancer activity through the inhibition of kinases and microtubule assembly. Adv. Drug Deliv. Rev. 170, 1–10 (2021). https://doi.org/10.1002/adtp.202100058
  37. Maka, K.K., Shiminga, Z., Epemolud, O., Dinkova-Kostova, A.T., Wells, G., Gazaryan, I.G., Sakirollak, R., Mohd, Z., Pichika, M.R.: Synthesis and anti-inflammatory activity of novel 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-derived NRF2 activators. Preprint (Gad). http://dx.doi.org/10.2139/ssrn.4097876
  38. Khatri, C.K., Indalkar, K.S., Patil, C.R., Goyal, S.N., Chaturbhuj, G.U.: Novel 2-phenyl-4,5,6,7-tetrahydro[b]benzothiophene analogues as selective COX-2 inhibitors: design, synthesis, anti-inflammatory evaluation, and molecular docking studies. Bioorg. Med. Chem. Lett. 27(8), 1721–1726 (2017). https://doi.org/10.1016/j.bmcl.2017.02.076
  39. Cruz, R.M.D., Mendonça-Junior, F.J.B., de Mélo, N.B., Scotti, L., de Araújo, R.S.A., de Almeida, R.N., de Moura, R.O.: Thiophene-based compounds with potential anti-inflammatory activity. Pharmaceutics 14(7), 692 (2021). https://doi.org/10.3390/ph14070692
  40. A.C.V. Aguiar., R.O. Moura., J.F.B. Mendonça Junior., H.A.O. Rocha., R.B.G. Câmara., M.S.C. Schiavon.: Evaluation of the antiproliferative activity of 2-amino thiophene derivatives against human cancer cell lines, Biomed. Pharmacother. 84:403–414 (2016). https://doi.org/10.1016/j.biopha.2016.09.026
  41. Banerjee, K., Rai, V.R., Umashankar, M.: Effect of peptide-conjugated nanoparticles on cell lines. Prog. Biomater. 8, 11–21 (2019). https://doi.org/10.1007/s40204-019-0106-9
  42. Kouhestani, F., Dehabadi, F., Hasan Shahriari, M., Motamedian, S.R. Allogenic vs.: Synthetic granules for bone tissue engineering: an in vitro study. Prog. Biomater. 7, 133–141 (2018). https://doi.org/10.1007/s40204-018-0092-3
  43. Liao, X.; Huang, J.; Lin, W.; Long, Z.; Xie, Y.; Ma, W.: APTM, a thiophene heterocyclic compound, inhibits human colon cancer HCT116 cell proliferation through p53-dependent induction of apoptosis. DNA Cell Biol. 37(2), 119–128 (2018). https://doi.org/10.1089/dna.2017.3962
  44. Mutlu, D., Cakir, C., Ozturk, M., Arslan, S.: Anticancer and apoptotic effects of a polysaccharide extract isolated from Lactarius chrysorrheus Fr. in HepG2 and PANC-1 cell lines. Arch. Biol. Sci. 74, 315–324 (2022). Mutlu, D., Cakir, C., Ozturk, M., Arslan, S.: Anticancer and apoptotic effects of a polysaccharide extract isolated from Lactarius chrysorrheus Fr. in HepG2 and PANC-1 cell lines. Arch. Biol. Sci. 74, 315–324 (2022). https://doi.org/10.2298/ABS220803030M
  45. Elmongy, E. I., Attallah, N. G. M., Altwaijry, N., AlKahtani, M. M., & Henidi, H. A.: Design and synthesis of new thiophene/thieno[2,3-d] pyrimidines along with their cytotoxic biological evaluation as tyrosine kinase inhibitors in addition to their apoptotic and autophagic induction. Molecules, 27(1), 123 (2022). https://doi.org/10.3390/molecules27010123
  46. Yılmaz, C., Pirdawid, A.O., Babat, C.F., Konuş, M., Çetin, D., Kıvrak, A., Algso, M.A.S., Arslan, Ş., Mutlu, D., Otur, Ç., Kurt Kızıldoğan, A.: A thiophene derivative, 2-bromo-5-(2-(methylthio)phenyl) thiophene, has effective anticancer potential with other biological properties. ChemistrySelect 7(15), e202200784 (2022). https://doi.org/10.1002/slct.202200784
  47. Griess, P.: Bemerkungen zu der Abhandlung der HH. Weselsky und Benedikt „Ueber einige Azoverbindungen. Ber. Dtsch. Chem. Ges. 12, 426–428 (1879). https://doi.org/10.1002/cber.187901201117