Advertisement

Preparation of some novel imidazopyridine derivatives of indole as anticancer agents: one-pot multicomponent synthesis, biological evaluation and docking studies

  • Zohreh Bakherad
  • Maliheh Safavi
  • Saghi Sepehri
  • Afshin Fassihi
  • Hojjat Sadeghi-Aliabadi
  • Mohammad Bakherad
  • Hossein Rastegar
  • Bagher Larijani
  • Lotfollah SaghaieEmail author
  • Mohammad MahdaviEmail author
Article
  • 26 Downloads

Abstract

A series of novel imidazopyridine derivatives of indole has been synthesized. All the synthesized derivatives were evaluated for their antiproliferative activity against A-549, T-47D, Hep-G2 and MCF-7 human cancer cell lines. The results demonstrated that some of these derivatives exhibited moderate to excellent cytotoxic activities. Compounds 7a having a cyclohexyl ring substituted to the second amine of imidazopyridyl moiety and phenyl ring of the C-2 indole ring and 7f with a para-methylphenyl ring at the same position exhibited the highest activity against the A-594 cell line with IC50 of 11.48 μM and 10.66 μM, respectively. The results indicate that compounds 7a and 7f are more cytotoxic towards cancer cell lines compared with etoposide in vitro. In addition, compounds, 7d and 7j showed the most potent activity against Hep-G2, equal to etoposide as the standard drug. Also, most of the compounds were inactive against the T-47D and MCF-7 cell lines. The morphological analysis by the acridine orange/ethidium bromide double-staining test and flow cytometry analysis indicated that compounds 7a and 7f induced apoptosis in A-549 cells. Furthermore, in silico and in vitro results of the synthesized compounds showed good correlation with each other. Molecular docking results of the compounds of the 7ak series with the cyclohexyl ring substituted to the second amine of the imidazopyridyl moiety compared with the 7lt members with the t-butyl group at the same position confirmed the effect of the higher lipophilicity on hydrophobic interactions with the studied enzymes. Moreover, all the compounds showed higher affinity to tubulin than topoisomerase IIα enzyme.

Keywords

Anticancer agents Molecular docking One-pot synthesis Imidazopyridine ring 

Notes

Acknowledgements

This work was supported by grants from the Isfahan University of Medical Sciences and the Tehran University of Medical Sciences.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

11164_2019_3915_MOESM1_ESM.docx (5.3 mb)
Supplementary material 1 (DOCX 5425 kb)

References

  1. 1.
    H. Patel, N. Darji, J. Pillai, B. Patel, Int. J. Drug. Res. Tech. 2, 225 (2012)Google Scholar
  2. 2.
    S. Shaaban, A. Negm, E.E. Ibrahim, A.A. Elrazak, Oncol. Rev. 8, 246 (2014)CrossRefGoogle Scholar
  3. 3.
    J.M. Yi, X.F. Zhang, X.J. Huan, S.S. Song, W. Wang, Q.T. Tian, Y.M. Sun, Y. Chen, J. Ding, Y.Q. Wang, C.H. Yang, Z.H. Miao, Oncotarget 6, 8960 (2015)Google Scholar
  4. 4.
    K.E. Hevener, A.T. Verstak, K.E. Lutat, D.L. Riggsbee, J.W. Mooney, Acta Pharm. Sin. B 8(6), 844 (2018)CrossRefGoogle Scholar
  5. 5.
    D.S. Takur, Int. J. Pharm. Sci. Nanotechnol. 3(4), 1173 (2011)Google Scholar
  6. 6.
    N. Fani, A.K. Bordbar, Y. Ghayeb, S. Sepehri, J. Biomol. Struct. Dyn. 33(3), 471 (2015)CrossRefGoogle Scholar
  7. 7.
    N. Fani, A.K. Bordbar, Y. Ghayeb, S. Sepehri, J. Biomol. Struct. Dyn. 33(10), 2285 (2015)CrossRefGoogle Scholar
  8. 8.
    A. Basnet, P. Thapa, R. Karki, H. Choi, J.H. Choi, M. Yun, B.S. Jeong, Y. Jahng, Y. Na, W.J. Cho, Y. Kwon, C.S. Lee, E.S. Lee, Bioorg. Med. Chem. Lett. 20, 42 (2010)CrossRefGoogle Scholar
  9. 9.
    S. Shaaban, F. Sasse, R. Diestel, B. Hinkelmann, Y. Muthukumar, R.P. Verma, C. Jacob, Eur. J. Med. Chem. 58, 192 (2012)CrossRefGoogle Scholar
  10. 10.
    S. Shaaban, A. Negm, A.M. Ashmawy, D.M. Ahmed, L.A. Wessjohann, Eur. J. Med. Chem. 122, 55 (2016)CrossRefGoogle Scholar
  11. 11.
    S. Shaaban, D. Vervandier-Fasseur, P. Andreoletti, A. Zarrouk, P. Richard, A. Negm, G. Manolikakes, C. Jacob, M. Cherkaoui-Malki, Bioorg. Chem. 80, 43 (2018)CrossRefGoogle Scholar
  12. 12.
    P.C. Diao, K.H. Hong, Q. Li, M.J. Hu, Y.F. Ma, W.W. You, P.L. Zhao, Eur. J. Med. Chem. 134, 110 (2017)CrossRefGoogle Scholar
  13. 13.
    D.R. Kerzare, P.B. Khedekar, J. Pharmsci. Biosci. Res. 6(1), 144 (2016)Google Scholar
  14. 14.
    S. Suzan, Curr. Org. Chem. 21(20), 2068 (2017)Google Scholar
  15. 15.
    A.M. Metwally, S. Shaaban, B.F. Abdel-Wahab, G.A. El-Hiti, Curr. Org. Chem. 13(14), 1475 (2009)CrossRefGoogle Scholar
  16. 16.
    S.N. Baytas, N. Inceler, A. Yılmaz, A. Olgac, S. Menevse, E. Hamel, R. Bortolozzi, G. Viola, Bioorg. Med. Chem. 22, 3096 (2014)CrossRefGoogle Scholar
  17. 17.
    J.P. Perchellet, E.M. Perchellet, C.R. Singh, Anticancer Res. 34(4), 1643 (2014)Google Scholar
  18. 18.
    P. Chen, Y.X. Zhuang, P.C. Diao, F. Yang, S.Y. Wu, L. Lv, W.W. You, P.L. Zhao, Eur. J. Med. Chem. 162, 525 (2019)CrossRefGoogle Scholar
  19. 19.
    G.L. Regina, R. Bai, A. Coluccia, V. Famiglini, S. Pelliccia, S. Passacantilli, C. Mazzoccoli, V. Ruggieri, A. Verrico, A. Miele, L. Monti, M. Nalli, R. Alfonsi, L.D. Marcotullio, A. Gulino, B. Ricci, A. Soriani, A. Santoni, M. Caraglia, S. Porto, E.D. Pozzo, C. Martini, A. Brancale, L. Marinelli, E. Novellino, S. Vultaggio, M. Varasi, C. Mercurio, C. Bigogno, G.M. Dondio, E. Hamel, P. Lavia, R. Silvestri, J. Med. Chem. 58(15), 5789 (2015)CrossRefGoogle Scholar
  20. 20.
    A.V. Subba Rao, M.V. Vishnu Vardhan, N.V. Subba Reddy, T. Srinivasa Reddy, S.P. Shaik, C. Bagul, A. Kamal, Bioorg. Chem. 69, 7 (2016)CrossRefGoogle Scholar
  21. 21.
    T.S. Harrison, G.M. Keating, CNS Drugs 19, 65 (2005)CrossRefGoogle Scholar
  22. 22.
    S. Shaaban, B.F. Abdel-Wahab, Mol Divers. 20(1), 233 (2016)CrossRefGoogle Scholar
  23. 23.
    K. Okseon, J. Yujeong, H. Lee, S.S. Hong, S. Hong, J. Med. Chem. 54, 2455 (2011)CrossRefGoogle Scholar
  24. 24.
    A. Kamal, V.S. Reddy, S. Karnewar, S.S. Chourasiya, A.B. Shaik, G.B. Kumar, C. Kishor, M.K. Reddy, M.P. Narasimha Rao, A. Nagabhushana, K.V. Ramakrishna, A. Addlagatta, S. Kotamraju, Chem. Med. Chem. 8(12), 2015 (2013)CrossRefGoogle Scholar
  25. 25.
    A.T. Baviskar, C. Madaan, R. Preet, P. Mohapatra, V. Jain, A. Agarwal, S.K. Guchhait, C.N. Kundu, U.C. Banerjee, P.V. Bharatam, J. Med. Chem. 54, 5013 (2011)CrossRefGoogle Scholar
  26. 26.
    K.T. Ashitha, C.T.F. Salfeena, J. Renjitha, V.P. Kumar, R. Parveen, B.S. Sasidhar, Curr. Bioact. Compd. 14(4), 445 (2018)CrossRefGoogle Scholar
  27. 27.
    Z. Bakherad, M. Safavi, A. Fassihi, H. Sadeghi-Aliabadi, M. Bakherad, H. Rastegar, J.B. Ghasemi, S. Sepehri, L. Saghaie, M. Mahdavi, Res. Chem. Intermed. 45(5), 2827 (2019)CrossRefGoogle Scholar
  28. 28.
    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
  29. 29.
    S. Sepehri, S. Soleymani, R. Zabihollahi, M.R. Aghasadeghi, M. Sadat, L. Saghaie, A. Fassihi, Chem. Biodivers. 14(12), e1700295 (2017)CrossRefGoogle Scholar
  30. 30.
    T. Akbarzadeh, S. Noushini, S. Taban, M. Mahdavi, M. Khoshneviszadeh, M. Saeedi, Mol. Divers. 19, 273 (2015)CrossRefGoogle Scholar
  31. 31.
    M. Safavi, A. Ashtari, F. Khalili, S.S. Mirfazli, M. Saeedi, S. Ardestani, K.P. Ranjbar, R.M. Barazandeh Tehrani, B. Larijani, M. Mahdavi, Chem. Biol. Drug. Des. 92(1), 1373 (2018)CrossRefGoogle Scholar
  32. 32.
    S. Sepehri, L. Saghaie, A. Fassihi, Mol. Inform. 36(3), 1 (2017)CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • Zohreh Bakherad
    • 1
    • 5
  • Maliheh Safavi
    • 2
  • Saghi Sepehri
    • 3
  • Afshin Fassihi
    • 1
  • Hojjat Sadeghi-Aliabadi
    • 1
  • Mohammad Bakherad
    • 4
  • Hossein Rastegar
    • 5
  • Bagher Larijani
    • 6
  • Lotfollah Saghaie
    • 1
    Email author
  • Mohammad Mahdavi
    • 6
    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.Department of Medicinal Chemistry, School of PharmacyArdabil University of Medical SciencesArdabilIran
  4. 4.School of ChemistryShahrood University of TechnologyShahroodIran
  5. 5.Food and Drug Control LaboratoriesFood and Drug Laboratory Research Center, MOE and METehranIran
  6. 6.Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Research InstituteTehran University of Medical SciencesTehranIran

Personalised recommendations