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Synthesis and Biological Evaluation of 2-(6-Phenylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzo[d]thiazole Derivatives as EGFR Targeting Anticancer Agents

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Abstract

ctive: Benzothiazole and imidazo[2,1-b][1,3,4]thiadiazole derivatives are the most important pharmacophores and intermediates for making drugs. This study focuses on the preparation and anti-cancer activity of novel benzothiazole-based imidazo[2,1-b][1,3,4]thiadiazole scaffolds. Methods: The synthesized benzothiazolebased imidazo[2,1-b][1,3,4]thiadiazole scaffolds (Va–Vi) were evaluated. The anticancer activity of (Va–Vi) against MCF-7 and A549 cell lines was determined using the MTT assay and screened with in silico molecular docking studies. Results and Discussion: Compounds 2-(6-(4-chlorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzo[d]thiazole (Vb), 2-(6-(4-bromophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzo[d]thiazole (Vd), and 2-(6-(4nitrophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzo[d]thiazole (Vh) exhibited the most potent anticancer activity against MCF-7 and A549 cancer cell lines. Molecular docking studies of all synthesized compounds and erlotinib were also carried out on the EGFR receptor, showing that compounds (Vb), (Vd), and (Vh) had significantly higher binding scores and inhibitory constants than the reference drug erlotinib. Conclusions: It has been observed that the substitution on the 4-chlorophenyl ring (Vb), 4-bromophenyl ring (Vd), and 4-nitrophenyl ring (Vh) is important for maintaining their anticancer activity. The outcomes of the kinase inhibitory assay of these significant (Vb), (Vd), and (Vh) hybrids against the tyrosine kinase EGFR strongly corroborated the in vitro anticancer findings and the in silico docking investigations. The investigation demonstrated that the newly synthesized compounds have the potential as anticancer agents and provided leads for further development.

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DATA AVAILABILITY

The data that support the findings of this study are available from the corresponding author upon reasonable request.

REFERENCES

  1. Ewes, W.A., Elmorsy, M.A., El-Messery, S.M., and Nasr, M.N.A., Bioorg. Med. Chem., 2020, vol. 28, p. 115373. https://doi.org/10.1016/j.bmc.2020.115373

    Article  CAS  PubMed  Google Scholar 

  2. Hassan, G.S., Georgey, H.H., Mohammed, E.Z., George, R.F., Mahmoud, W.R., and Omar, F.A., Eur. J. Med. Chem., 2021, vol. 218, p. 113389. https://doi.org/10.1016/j.ejmech.2021.113389

    Article  CAS  PubMed  Google Scholar 

  3. Shafei, A., El-Bakly, W., Sobhy, A., Wagdy, O., Reda, A., Aboelenin, O., Marzouk, A., El Habak, K., Mostafa, R., Ali, M.A., and Ellithy, M., Biomed. Pharmacother., 2017, vol. 95, pp. 1209−1218. https://doi.org/10.1016/j.biopha.2017.09.059

    Article  CAS  PubMed  Google Scholar 

  4. Hashem, H.E., Amr, A.E.G.E., Nossier, E.S., Anwar, M.M., and Azmy, E.M., ACS Omega, 2022, vol. 7, pp. 7155–7171. https://doi.org/10.1021/acsomega.1c06836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kim, M., Baek, M., and Kim, D.J., Curr. Pharm. Des., 2017, vol. 23, pp. 4226−4246. https://doi.org/10.2174/1381612823666170616082125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Rezki, N., Almehmadi, M.A., Ihmaid, S., Shehata, A.M., Omar, A.M., Ahmed, H.E., and Aouad, M.R., Bioorg. Chem., 2020, vol. 103, p. 104133. https://doi.org/10.1016/j.bioorg.2020.104133

    Article  CAS  PubMed  Google Scholar 

  7. Othman, I.M.M., Alamshany, Z.M., Tashkandi, N.Y., GadElkareem, M.A.M., Anwar, M.M., and Nossier, E., Bioorg. Chem., 2021, vol. 114, p. 105078. https://doi.org/10.1016/j.bioorg.2021.105078

    Article  CAS  PubMed  Google Scholar 

  8. Abd El-Meguid, E.A., Moustafa, G.O., Awad, H.M., Zaki, E.R., and Nossier, E.S., J. Mol. Struct., 2021, vol. 1240, p. 130595. https://doi.org/10.1016/j.molstruc.2021.130595

    Article  CAS  Google Scholar 

  9. Ahmed, M.F., Santali, E.Y., El-Deen, E.M.M., Naguib, I.A., and El-Haggar, R., Bioorg. Chem., 2021, vol. 106, p. 104473. https://doi.org/10.1016/j.bioorg.2020.104473

    Article  CAS  PubMed  Google Scholar 

  10. Eshacharyulu, P., Ponnusamy, M.P., Haridas, D., Jain, M., Ganti, A.K., and Batra, S.K., Exp. Opin. Ther. Target., 2012, vol. 16, pp. 15−31. https://doi.org/10.1517/14728222.2011.648617

    Article  CAS  Google Scholar 

  11. Deng, X., Tan, X., An, T., Ma, Q., Jin, Z., Wang, C., Meng, Q., and Hu, C., Molecules, 2019, vol. 24, p. 682. https://doi.org/10.3390/molecules24040682

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Meier, F., Schittek, B., Busch, S., Garbe, C., Smalley, K., Satyamoorthy, K., Li, G., and Herlyn, M., Front. Biosci.– Landmark, 2005, vol. 10, pp. 2986–3001.

    Article  CAS  Google Scholar 

  13. Asif, M. and Imran, M., Mini-Rev. Org. Chem., 2021, vol. 18, pp. 1086–1097. https://doi.org/10.2174/1570193X17999201127110214

    Article  CAS  Google Scholar 

  14. Kurt, A.H., Ayaz, L., Ayaz, F., Seferoglu, Z., and Nural, Y., Curr. Org. Syn., 2022, vol. 19, pp. 772–796. https://doi.org/10.2174/1570179419666220330001036

    Article  CAS  Google Scholar 

  15. Haider, K., Rehman, S., Pathak, A., Najmi, A.K., and Yar, M.S., Arch. der Pharmazie, 2021, vol. 354, p. 2100246. https://doi.org/10.1002/ardp.202100246

    Article  CAS  Google Scholar 

  16. Djuidje, E.N., Barbari, R., Baldisserotto, A., Durini, E., Sciabica, S., Balzarini, J., Liekens, S., Vertuani, S., and Manfredini, S., Antioxidants, 2022, vol. 11, p. 407. https://doi.org/10.3390/antiox11020407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kumar, G. and Singh, N.P., Bioorg. Chem., 2021, vol. 107, p. 104608. https://doi.org/10.1016/j.bioorg.2020.104608

    Article  CAS  PubMed  Google Scholar 

  18. Venugopala, K.N., Chandrashekharappa, S., Pillay, M., Bhandary, S., Kandeel, M., Mahomoodally, F.M., Morsy, M.A., Chopra, D., Aldhubiab, B.E., Attimarad, M., and Alwassil, O.I., Med. Chem., 2019, vol. 15, pp. 311–326. https://doi.org/10.2174/1573406414666180703121815

    Article  CAS  PubMed  Google Scholar 

  19. Thakkar, S.S., Thakor, P., Ray, A., Doshi, H., and Thakkar, V.R., Bioorg. Med. Chem., 2017, vol. 25, pp. 5396–5406. https://doi.org/10.1016/j.bmc.2017.07.057

    Article  CAS  PubMed  Google Scholar 

  20. Asiri, Y.I., Alsayari, A., Muhsinah, A.B., Mabkhot, Y.N., and Hassan, M.Z., J. Pharm. Pharmacol., 2020, vol. 72, pp. 1459–1480. https://doi.org/10.1111/jphp.13331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bhagdev, K. and Sarkar, S., Annal. Rom. Soc. Cell Biol., 2021, vol. 25, pp. 20269–20285. http://www.annalsofrscb.ro/index.php/journal/article/view/9199

    Google Scholar 

  22. Nath, R., Yar, M.S., Pathania, S., Grover, G., Debnath, B., and Akhtar, M.J., J. Mol. Struct., 2021, vol. 1228, p. 129742. https://doi.org/10.1016/j.molstruc.2020.129742

    Article  CAS  Google Scholar 

  23. Singh, M.K., Tilak, R., Nath, G., Awasthi, S.K., and Agarwal, A., Eur. J. Med. Chem., 2013, vol. 63, pp. 635–644. https://doi.org/10.1016/j.ejmech.2013.02.027

    Article  CAS  PubMed  Google Scholar 

  24. Irfan, A., Batool, F., Zahra Naqvi, S.A., Islam, A., Osman, S.M., Nocentini, A., Alissa, S.A., and Supuran, C.T., J. Enzyme Inhib. Med. Chem., 2020, vol. 35, pp. 265–279. https://doi.org/10.1080/14756366.2019.1698036

    Article  CAS  PubMed  Google Scholar 

  25. Saeed, S., Rashid, N., Jones, P.G., Ali, M., and Hussain, R., Eur. J. Med. Chem., 2010, vol. 45, pp. 1323–1331. https://doi.org/10.1016/j.ejmech.2009.12.016

    Article  CAS  PubMed  Google Scholar 

  26. Abdelgawad, M.A., Belal, A., Omar, H.A., Hegazy, L., and Rateb, M.E., Arch. der. Pharmazie, 2013, vol. 346, pp. 534–541. https://doi.org/10.1002/ardp.201300044

    Article  CAS  Google Scholar 

  27. Gabr, M.T., El-Gohary, N.S., El-Bendary, E.R., and El-Kerdawy, M.M., Med. Chem. Res., 2015, vol. 24, pp. 860–878. https://doi.org/10.1007/s00044-014-1114-x

    Article  CAS  Google Scholar 

  28. Abdellatif, K.R., Belal, A., El-Saadi, M.T., Amin, N.H., Said, E.G., and Hemeda, L.R., Bioorg. Chem., 2020, vol. 101, p. 103976. https://doi.org/10.1016/j.bioorg.2020.103976

    Article  CAS  PubMed  Google Scholar 

  29. Gabr, M.T., El-Gohary, N.S., El-Bendary, E.R., and El-Kerdawy, M.M., EXCLI J., 2014, vol. 13, pp. 573–585. https://www.excli.de/index.php/excli/article/view/723

    PubMed  PubMed Central  Google Scholar 

  30. Bhongade, B.A., Talath, S., Gadad, R.A., and Gadad, A.K., J. Saudi Chem. Soc., 2016, vol. 20, pp. S463–S475. https://doi.org/10.1016/j.jscs.2013.01.010

  31. Khan, I., Ibrar, A., and Abbas, N., Eur. J. Med. Chem., 2013, vol. 63, pp. 854–868. https://doi.org/10.1016/j.ejmech.2013.01.060

    Article  CAS  PubMed  Google Scholar 

  32. Cristina, A., Leonte, D., Vlase, L., Bencze, L.C., Imre, S., Marc, G., Apan, B., Mogoșan, C., and Zaharia, V., Molecules, 2018, vol. 23, p. 2425. https://doi.org/10.3390/molecules23102425

  33. Dagli, M., Er, M., Karakurt, T., Onaran, A., Alici, H., and Tahtaci, H., ChemistrySelect, 2020, vol. 5, pp. 11753–11763. https://doi.org/10.1002/slct.202002821

    Article  CAS  Google Scholar 

  34. Yan Guo, F., Ji Zheng, C., Wang, M., Ai, J., Ying Han, L., Yang, L., Fang Lu, Y., Xuan Yang, Y., Guan Piao, M., Piao, H.R., and Jin, C.M., ChemMedChem, 2021, vol. 16, pp. 2354–2365. https://doi.org/10.1002/cmdc.202100122

    Article  CAS  PubMed  Google Scholar 

  35. Er, M., Özer, A., Direkel, Ş., Karakurt, T., and Tahtaci, H., J. Mol. Struct., 2019, vol. 1194, pp. 284–296. https://doi.org/10.1016/j.molstruc.2019.05.104

    Article  CAS  Google Scholar 

  36. Er, M., Ergüven, B., Tahtaci, H., Onaran, A., Karakurt, T., and Ece, A., Med. Chem. Res., 2017, vol. 26, pp. 615–630. https://doi.org/10.1007/s00044-017-1782-4

    Article  CAS  Google Scholar 

  37. Taflan, E., Bayrak, H., Er, M., Karaoğlu, Ş.A., and Bozdeveci, A., Bioorg. Chem., 2019, vol. 89, p. 102998. https://doi.org/10.1016/j.bioorg.2019.102998

    Article  CAS  PubMed  Google Scholar 

  38. Dincel, E.D., Gürsoy, E., Yilmaz-Ozden, T., and UlusoyGüzeldemirci, N., Bioorg. Chem., 2020, vol. 103, p. 104220. https://doi.org/10.1016/j.bioorg.2020.104220

    Article  CAS  PubMed  Google Scholar 

  39. Haider, S., Alam, M.S., and Hamid, H., Eur. J. Med. Chem., 2015, vol. 92, pp. 156–177. https://doi.org/10.1016/j.ejmech.2014.12.035

    Article  CAS  PubMed  Google Scholar 

  40. Cascioferro, S, Parrino, B, Petri, G.L., Cusimano, M.G., Schillaci, D., Di Sarno, V., Musella, S., Giovannetti, E., Cirrincione, G., and Diana, P., Eur. J. Med. Chem., 2019, vol. 167, pp. 200–210. https://doi.org/10.1016/j.ejmech.2019.02.007

    Article  CAS  PubMed  Google Scholar 

  41. Turner, S., Myers, M., Gadie, B., Hale, S.A., Horsley, A., Nelson, A.J., Pape, R., Saville, J.F., Doxey, J.C., and Berridge, T.L., J. Med. Chem., 1988, vol. 31, pp. 906–913. https://doi.org/10.1021/jm00400a004

    Article  CAS  PubMed  Google Scholar 

  42. Andreani, A., Leoni, A., Locateur, A., Morigi, R., Rambaldi, M., Simon, W.A., and Senn-Bilfinger, J., Arzneimittelforschung, 2000, vol. 50, pp. 550–553. https://doi.org/10.1055/s-0031-1300247

    Article  CAS  PubMed  Google Scholar 

  43. Palabindela, R., Guda, R., Ramesh, G., Bodapati, R., Nukala, S.K., Myadaraveni, P., Ravi, G., and Kasula, M., J. Mol. Struct., 2023, vol. 1275, p. 134633. https://doi.org/10.1016/j.molstruc.2022.134633

    Article  CAS  Google Scholar 

  44. Ramya Sucharitha, E., Kumar Nukala, S., Swamy Thirukovela, N., Palabindela, R., Sreerama, R., and Narsimha, S., ChemistrySelect, 2023, vol. 8, p. e202204256. https://doi.org/10.1002/slct.202204256

  45. Ismael, A.S., Amin, N.H., Elsaadi, M.T., and AbdelRahman, H.M., Bioorg. Chem., 2022, vol. 128, p. 106042. https://doi.org/10.1016/j.bioorg.2022.106042

    Article  CAS  PubMed  Google Scholar 

  46. Park, J.H., Liu, Y., Lemmon, M.A., and Radhakrishnan, R., Biochem. J., 2022, vol. 448, pp. 417–423. https://doi.org/10.1042/BJ20121513

    Article  CAS  Google Scholar 

  47. https://www.rcsb.org/structure/4HJO

  48. Palabindela, R., Guda, R., Ramesh, G., Myadaraveni, P., Banothu, D., Ravi, G., Korra, R., Mekala, H., and Kasula, M., J. Heterocyc. Chem., vol. 59, pp. 1533–1550. https://doi.org/10.1002/jhet.4488

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ACKNOWLEDGMENTS

The authors are thankful to the head of the Department of Pharmaceutical Science at Kakatiya University, Warangal, for providing biological activity data. Grateful to the Director, IICT-Hyderabad, for providing spectral data.

Funding

This work was supported by regular institutional funding, and no additional grants were obtained.

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Authors and Affiliations

  1. Department of Chemistry, S.R.R. Government Arts and Science (Autonomous) College, Karimnagar, 505001, Telangana, India

    Boda Mahipal Reddy, Midde Sridhar, Mekala Himabindu, K. Bhaskar & G. V. R. Sai Madhukar

  2. Department of Chemistry, Kakatiya University, 506009, Warangal, India

    Mekala Himabindu & Mamatha Kasula

  3. Department of Chemistry, S.K.N.R. Government Arts and Science College, Jagtial, Satavahana University, Karimnagar, 505327, Telangana, India

    T. Karunakar

  4. University of Massachusetts Chan Medical School, RNA therapeutics Institute, Worcester, 01655, Massachusetts, USA

    Sudhakar Reddy Baddam

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  1. Boda Mahipal Reddy
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Contributions

The author BMR is involved in the methodology, investigation, and data curation. The author MS is involved in the designed chemistry part and manuscript language editing process; the author MH is involved in the molecular docking studies; the author KB is involved in the experimental data; the authors GVRSM and SRB is participated in the in vitro anticancer studies. The author TK is involved in the manuscript language editing process. The author MK is involved in the supervision of manuscript writing etc.

All authors participated in the discussions.

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Correspondence to Mamatha Kasula.

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Reddy, B.M., Sridhar, M., Himabindu, M. et al. Synthesis and Biological Evaluation of 2-(6-Phenylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)benzo[d]thiazole Derivatives as EGFR Targeting Anticancer Agents. Russ J Bioorg Chem 50, 571–581 (2024). https://doi.org/10.1134/S1068162024020146

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