Research on Chemical Intermediates

, Volume 45, Issue 5, pp 2827–2854 | Cite as

Anti-cancer, anti-oxidant and molecular docking studies of thiosemicarbazone indole-based derivatives

  • Zohreh Bakherad
  • Maliheh Safavi
  • Afshin Fassihi
  • Hojjat Sadeghi-Aliabadi
  • Mohammad Bakherad
  • Hossein Rastegar
  • Jahan B. Ghasemi
  • Saghi Sepehri
  • Lotfollah SaghaieEmail author
  • Mohammad MahdaviEmail author


Based on the structural elements of bioactive 3-substituted indoles, a new series of indole–thiosemicarbazone hybrid derivatives were designed, synthesized, and well-characterized using different spectral techniques. The intended scaffolds were screened for their in vitro anti-proliferative activities against breast cancer (MCF-7), lung cancer (A-549), and liver cancer (Hep-G2) cell lines, as well as their anti-oxidant properties. Cytotoxicity studies revealed that compound 6n was the most potent, at least threefold more potent than the commercially available reference drug etoposide, against A-549. In addition, morphological analysis by the acridine orange/ethidium bromide double staining test and flow cytometry analysis confirmed induction of apoptosis in the A-549 cells by compound 6n. In order to validate the experimental results, molecular studies were performed to achieve the possible binding interactions of the most potent compound (6n) and colchicine with tubulin as well as ANP with ATPase domain of topoisomerase IIα active sites. Moreover, the radical scavenging potential of the final derivatives was found to be excellent with the range of 0.015–0.630 µM, comparable to the standard ascorbic acid (0.655 µM).


Indole Thiosemicarbazone Anti-oxidant Anti-cancer Apoptosis Flow cytometry 



This work was supported by Grants from Isfahan university of Medical Sciences and Tehran University of Medical Sciences.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interests.

Supplementary material

11164_2019_3765_MOESM1_ESM.docx (2.7 mb)
Supplementary material 1 (DOCX 2759 kb)


  1. 1.
    X. Zhang, K.P. Rakesh, C.S. Shantharam, H.M. Manukumar, A.M. Asiri, H.M. Marwani, H.L. Qin, Bioorg. Med. Chem. 26, 340 (2017)CrossRefGoogle Scholar
  2. 2.
    G.F. Zha, H.L. Qin, B.G.M. Youssif, M.W. Amjad, M.A.G. Raja, A.H. Abdelazeem, S.N.A. Bukhari, Eur. J. Med. Chem. 135, 34 (2017)CrossRefGoogle Scholar
  3. 3.
    H.L. Qin, M.A. Ghafoor Raja, L. Jing, B.G.M. Youssif, M.W. Amjad, S.N.A. Bukhari, M.A. Hussain, Z. Hussain, S.N. Kazmi, Chem. Biol. Drug Des. 90(3), 443 (2017)CrossRefGoogle Scholar
  4. 4.
    J.F. de Oliveira, T.S. Lima, D.B. Vendramini-Costa, S.C.B. de Lacerda Pedrosa, E.A. Lafayette, R.M.F. da Silva, S.M.V. de Almeida, R.O. de Moura, A.L.T.G. Ruiz, J. Ernesto de Carvalho, M.C. Alves de Lima, Eur. J. Med. Chem. 136, 305 (2017)CrossRefGoogle Scholar
  5. 5.
    J.F. de Oliveira, A.L. da Silva, D.B. Vendramini-Costa, C.A. da Cruz Amorim, J.F. Campos, A.G. Ribeiro, R.O. de Moura, J.L. Neves, A.L.T.G. Ruiz, J.E. de Carvalho, M.D.C.A. de Lima, Eur. J. Med. Chem. 104, 148 (2015)CrossRefGoogle Scholar
  6. 6.
    P.R. Kamath, D. Sunil, A.A. Ajees, K.S.R.S. Pai, Bioorg. Chem. 63, 101 (2015)CrossRefGoogle Scholar
  7. 7.
    A. Negi, J.M. Alex, S.M. Amrutkar, A.T. Baviskar, G. Joshi, S. Singh, U.C. Banerjee, R. Kumar, Bioorg. Med. Chem. 23, 5654 (2015)CrossRefGoogle Scholar
  8. 8.
    C. Zhao, K.P. Rakesh, S. Mumtaz, B. Moku, A.M. Asiri, H.M. Marwani, H.M. Manukumar, H.L. Qin, RSC Adv. 8, 9487 (2018)CrossRefGoogle Scholar
  9. 9.
    K.P. Rakesh, C.S. Shantharam, M.B. Sridhara, H.M. Manukumar, H.L. Qin, Med. Chem. Commun. 8, 2023 (2017)CrossRefGoogle Scholar
  10. 10.
    H.L. Qin, Z.P. Shang, I. Jantan, O.U. Tan, M.A. Hussain, M. Sher, S.N.A.Bukhari, RSC Adv. 5, 46330 (2015)CrossRefGoogle Scholar
  11. 11.
    C. Zhao, K. Rakesh, L. Ravidar, W.Y. Fang, Eur. J. Med. Chem. 162, 679 (2019)CrossRefGoogle Scholar
  12. 12.
    K.P. Rakesh, S.M. Wang, J. Leng, L. Ravindar, A.M. Asiri, H.M. Marwani, H.L. Qin, Anticancer Agents Med. Chem. 18(4), 488 (2018)CrossRefGoogle Scholar
  13. 13.
    S.M. Wang, G.F. Zha, K.P. Rakesh, N. Darshini, T. Shubhavathi, H.K. Vivek, N. Mallesha, H.L. Qin, Med. Chem. Commun. 8, 1173 (2017)CrossRefGoogle Scholar
  14. 14.
    H.L. Qin, J. Leng, C.P. Zhang, I. Jantan, M.W. Amjad, M. Sher, M. Naeem-ul-Hassan, M.A. Hussain, S.N.A. Bukhari, J. Med. Chem. 59(7), 3549 (2016)CrossRefGoogle Scholar
  15. 15.
    A. Ozdemir, M.D. Altıntop, G. Turan-Zitouni, G.A. Çiftçi, I. Ertorun, O. Alatas, Z.A. Kaplancıklı, Eur. J. Med. Chem. 89, 304 (2015)CrossRefGoogle Scholar
  16. 16.
    M. Zhang, Q. Chen, G. Yang, Eur. J. Med. Chem. 89, 421 (2015)CrossRefGoogle Scholar
  17. 17.
    N.T. Tzvetkov, S. Hinz, P. Küppers, M. Gastreich, C.E. Müller, J. Med. Chem. 57(15), 6679 (2014)CrossRefGoogle Scholar
  18. 18.
    S. Kumar, S. Mehndiratta, K. Nepali, M.K. Gupta, S. Koul, P.R. Sharma, A.K. Saxena, K.L. Dhar, Org. Med. Chem. Lett. 3(1), 3 (2017)CrossRefGoogle Scholar
  19. 19.
    Z. Datong, X. Rongrong, G. Shoudong, Z. Yaling, Res. Chem. Intermed. 41(9), 6575 (2015)CrossRefGoogle Scholar
  20. 20.
    G. De Martino, M.C. Edler, G. La Regina, A. Coluccia, M.C. Barbera, D. Barrow, R.I. Nicholson, G. Chiosis, G. La Regina, A. Brancale, A. Coluccia, E. Hamel, M. Artico, R. Silvestri, J. Med. Chem. 49, 947 (2006)CrossRefGoogle Scholar
  21. 21.
    S.N. Baytas, N. Inceler, A. Yılmaz, A. Olgac, E. Banoglu, E. Hamel, R. Bortolozzi, G. Viola, S. Menevse, Bioorg. Med. Chem. 22, 3096 (2014)CrossRefGoogle Scholar
  22. 22.
    R.S. Patil, A. Patil, K.D. Beaman, S.A. Patil, Future Med. Chem. 8(11), 1291 (2016)CrossRefGoogle Scholar
  23. 23.
    R. Gastpar, M. Goldbrunner, D. Marko, E. Angerer, J. Med. Chem. 41, 4965 (1998)CrossRefGoogle Scholar
  24. 24.
    D. Kaufmann, M. Pojarova, S. Vogel, R. Liebl, R. Gastpar, D. Gross, T. Nishino, T. Pfaller, E. Angerer, Bioorg. Med. Chem. 15, 5122 (2007)CrossRefGoogle Scholar
  25. 25.
    E.A. Britta, D.B. Scariot, H. Falzirolli, T. Ueda-Nakamura, C.C. Silva, B.P. Dias Filho, R. Borsali, C.V. Nakamura, BMC Microbiol. 14, 236 (2014)CrossRefGoogle Scholar
  26. 26.
    M.A. Souza, S. Juhann, L.A.R.D.S. Lima, F.F. Campos, I.C. Mendes, H. Beraldo, E.M.D. Souza-Fagundes, P.S. Cisalpino, C.A. Rosa, T.M.D.A. Alves, N.P.D. Sa, C.L. Zani, Mem. Inst. Oswaldo Cruz 108(3), 342 (2013)CrossRefGoogle Scholar
  27. 27.
    A.S. Salman, N.A. Mahmoud, M.A. Mohamed, A. Abdel-Aziem, D.M. Elsisi, Am. J. Org. Chem. 6(2), 39 (2016)Google Scholar
  28. 28.
    S.M.V. de Almeida, E.A. Lafayette, L.P.B.G. da Silva, C.A.D.C. Amorim, T.B. de Oliveira, A.L.T.G. Ruiz, J.E. de Carvalho, R.O. de Moura, E.I.C. Beltrão, M.D.C.A. de Lima, L.B.D.C. Júnior, Int. J. Mol. Sci. 16, 13023 (2015)CrossRefGoogle Scholar
  29. 29.
    B. Xu, Y. Yu, P. Wan, Res. Chem. Intermed. 40, 3095 (2014)CrossRefGoogle Scholar
  30. 30.
    H. Huang, Q. Chen, X. Ku, L. Meng, L. Lin, X. Wang, C. Zhu, Y. Wang, Z. Chen, M. Li, H. Jiang, K. Chen, J. Ding, H. Liu, J. Med. Chem. 53, 3048 (2010)CrossRefGoogle Scholar
  31. 31.
    C. Karaaslan, H. Kadri, T. Coban, S. Suzen, Bioorg. Med. Chem. Lett. 23, 2671 (2013)CrossRefGoogle Scholar
  32. 32.
    V. Mashayekhi, K. Haj Mohammad Ebrahim Tehrani, P. Azerang, S. Sardari, F. Kobarfard, Arch. Pharmacal. Res. 1 (2013)Google Scholar
  33. 33.
    Z. Liu, S. Wu, Y. Wang, R. Li, J. Wang, L. Wang, Y. Zhao, P. Gong, Eur. J. Med. Chem. 87, 782 (2014)CrossRefGoogle Scholar
  34. 34.
    M. Safavi, N. Esmati, S.K. Ardestani, S. Emami, S. Ajdari, J. Davoodi, A. Shafiee, A. Foroumadi, Eur. J. Med. Chem. 58, 573 (2012)CrossRefGoogle Scholar
  35. 35.
    A.H. Halawa, A.A.E.H. Hassan, M.A. El-Nassag, M.M.A. El-All, G.E.R.A. El-Jaleel, E.M. Eliwa, A.H. Bedair, Eur. J. Chem. 5(1), 111 (2014)CrossRefGoogle Scholar
  36. 36.
    N. Liang, D.D. Kitts, Molecules 19, 19180 (2014)CrossRefGoogle Scholar
  37. 37.
    S. Sepehri, S. Soleymani, R. Zabihollahi, M.R. Aghasadeghi, M. Sadat, L. Saghaie, A. Fassihi, Chem. Biodivers. 14, e1700295 (2017)CrossRefGoogle Scholar
  38. 38.
    M. Safavi, A. Ashtari, F. Khalili, S.S. Mirfazli, M. Saeedi, S. Ardestani, K.P. Ranjbar, R.M.B. Tehrani, B. Larijani, M. Mahdavi, Chem. Biol. Drug Des. 92, 1373 (2018)CrossRefGoogle Scholar
  39. 39.
    M. Volovenko, E.V. Resnyanska, Mendel Commun. 12, 119 (2002)CrossRefGoogle Scholar
  40. 40.
    N. Mahmoodi, S. Ghodsi, Res. Chem. Intermed. 43(2), 661 (2017)CrossRefGoogle Scholar
  41. 41.
    F.A. Momany, R. Rone, J. Comput. Chem. 13, 888 (1992)CrossRefGoogle Scholar
  42. 42.

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • Zohreh Bakherad
    • 1
  • Maliheh Safavi
    • 2
  • Afshin Fassihi
    • 1
  • Hojjat Sadeghi-Aliabadi
    • 1
  • Mohammad Bakherad
    • 3
  • Hossein Rastegar
    • 4
  • Jahan B. Ghasemi
    • 5
  • Saghi Sepehri
    • 6
  • Lotfollah Saghaie
    • 1
    Email author
  • Mohammad Mahdavi
    • 7
    Email author
  1. 1.Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical SciencesIsfahan University of Medical SciencesIsfahanIran
  2. 2.Department of BiotechnologyIranian Research Organization for Science and TechnologyTehranIran
  3. 3.School of ChemistryShahrood University of TechnologyShahroodIran
  4. 4.Food and Drug Control Laboratories, Food and Drug Laboratory Research CenterMOE and METehranIran
  5. 5.Drug Design in Silico Lab, Chemistry Faculty, School of SciencesUniversity of TehranTeheranIran
  6. 6.Department of Medicinal Chemistry, School of PharmacyArdabil University of Medical SciencesArdabilIran
  7. 7.Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Research InstituteTehran University of Medical SciencesTehranIran

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