Skip to main content
SpringerLink
Log in

Synthesis, antimycobacterial and anticancer activity of novel indole-based thiosemicarbazones

  • Research Article
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

Based on the structural elements of bioactive indole-based compounds, a series of novel 1-substituted indole-3-carboxaldehyde thiosemicarbazones were synthesized as potential antimycobacterial and anticancer agents. The derivatives were prepared via a two-step methodology including N-alkylation(benzylation) of indole-3-carboxaldehyde and conversion of the intermediate aldehydes to corresponding thiosemicarbazones. The derivatives were evaluated for their antimycobacterial activity and compounds 3d (R = propyl) and 3q (R = 4-nitrobenzyl) were among the most potent and selective derivatives with IC50 values of 0.9 and 1.9 μg/mL respectively. The anticancer activity of the derivatives was also assessed against a panel of tumor cell lines. Compounds 3t, 3u, 3v and 3w efficiently inhibited the majority of the cancer cell lines with considerable selectivity.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Scheme 1

Similar content being viewed by others

References

  • Bacchi, A., M. Carcelli, P. Pelagatti, C. Pelizzi, G. Pelizzi, and F. Zani. 1999. Antimicrobial and mutagenic activity of some carbon and thiocarbonohydrazone ligands and their copper(II), iron(II) and zinc(II) complexes. Journal of Inorganic Biochemistry 75: 123–133.

    Article  CAS  Google Scholar 

  • Banerjee, D., P. Yogeeswari, P. Bhat, A. Thomas, M. Srividya, and D. Sriram. 2011. Novel isatinyl thiosemicarbazones derivatives as potential molecule to combat HIV-TB co-infection. European Journal of Medicinal Chemistry 46: 106–121.

    Article  CAS  Google Scholar 

  • Battaglia, S., E. Boldrini, F.D. Settimo, G. Dondio, C.L. Motta, A.M. Marini, and G. Primofiore. 1999. Indole amide derivatives: synthesis, structure–activity relationships and molecular modelling studies of a new series of histamine H1-receptor antagonists. European Journal of Medicinal Chemistry 34: 93–105.

    Article  CAS  Google Scholar 

  • Borgne, M.L., P. Marchand, M. Duflos, B. Delevoye-Seiller, S. Piessard-Robert, G.L. Baut, R.W. Hartmann, and M. Palzer. 1997. Synthesis and in vitro evaluation of 3-(1-azolylmethyl)-1H-indoles and 3-(1-azolyl-1-phenylmethyl)-1H-indoles as inhibitors of P450 arom. Archiv der Pharmazie 330: 141–145.

    Article  Google Scholar 

  • Brancale, A., and R. Silvestri. 2007. Indole, a core nucleus for potent inhibitors of tubulin polymerization. Medicinal Research Reviews 27: 209–238.

    Article  CAS  Google Scholar 

  • Cavrini, V., R. Gatti, P. Roveri, M.R. Cesaroni, A. Mazzoni, and C. Fiorentini. 1984. Syntheses and in vitro antimycotic activities of 1-benzyl-3-(1-imidazolylmethyl)indoles. Archiv der Pharmazie 317: 662–668.

    Article  CAS  Google Scholar 

  • De Belin, J. Y., Romer Martin, M. R., Fin, P. W., Sayers, L. G., Law, N. M., Billington, D. C., Ryley, S., Bhattacharya, S. 2001. Patent no., WO 01/93841 A2.

  • Ewing, W.R., M.R. Becker, V.E. Manetta, R.S. Davis, H.W. Pauls, H. Mason, Y.M. Choi-Sledeski, D. Green, D. Cha, A.P. Spada, D.L. Cheney, J.S. Mason, S. Maignan, J.P. Guilloteau, K. Brown, D. Colussi, R. Bentley, J. Bostwick, C.J. Kasiewski, S.R. Morgan, R.J. Leadley, C.T. Dunwiddie, M.H. Perrone, and V. Chu. 1999. Design and structure – activity relationships of potent and selective inhibitors of blood coagulation factor Xa. Journal of Medicinal Chemistry 42: 3557–3571.

    Article  CAS  Google Scholar 

  • Glennon, R.A., C. Chaurasia, and M. Titeler. 1990. Binding of indolylalkylamines at 5-HT2 serotonin receptors: examination of a hydrophobic binding region. Journal of Medicinal Chemistry 33: 2777–2784.

    Article  CAS  Google Scholar 

  • Greenbaum, D.C., Z. Mackey, E. Hansell, P. Doyle, J. Gut, C.R. Caffrey, J. Lehrman, P.J. Rosenthal, J.H. McKerrow, and K. Chibale. 2004. Synthesis and structure – activity relationships of parasiticidal thiosemicarbazone cysteine protease inhibitors against Plasmodium falciparum, Trypanosoma brucei, and Trypanosoma cruzi. Journal of Medicinal Chemistry 47: 3212–3219.

    Article  CAS  Google Scholar 

  • Gupta, R.A., A.K. Gupta, L.K. Soni, and S.G. Kaskhedikar. 2007. Rationalization of physicochemical characters of oxazolyl thiosemicarbazone analogs towards multi-drug resistant tuberculosis: A QSAR approach. European Journal of Medicinal Chemistry 42: 1109–1116.

    Article  CAS  Google Scholar 

  • Haj Mohammad Ebrahim Tehrani, K., S. Sardari, V. Mashayekhi, M. Esfahani Zadeh, P. Azerang, and F. Kobarfard. 2013. One pot synthesis and biological activity evaluation of novel Schiff bases derived from 2-hydrazinyl-1,3,4-thiadiazole. Chemical and Pharmaceutical Bulletin 61: 160–166.

    Article  Google Scholar 

  • Halve, A.K., B. Bhashkar, V. Sharma, R. Bhadauria, A. Kankoriya, A. Soni, and K. Tiwari. 2008. Synthesis and in vitro antimicrobial studies of some new 3-[phenyldiazenyl] benzaldehyde N-phenyl thiosemicarbazones. Journal of Enzyme Inhibition and Medicinal Chemistry 23: 77–81.

    Article  CAS  Google Scholar 

  • Knaack, M., P. Emig, J.W. Bats, M. Kiesel, A. Müller, and E. Günther. 2001. Synthesis and characterization of the biologically active 2-[1-(4-chlorobenzyl)-1H-indol-3-yl]-2-oxo-N-pyridin-4-yl acetamide. European Journal of Organic Chemistry 20: 3843–3847.

    Article  Google Scholar 

  • Kobarfard, F., Kauffman, J. M. 2003. U. S. Patent 6482982.

  • Marcin, L.R., M.A. Higgins, F.C. Zusi, Y. Zhang, M.F. Dee, M.F. Parker, J.K. Muckelbauer, D.M. Camac, P.E. Morin, V. Ramamurthy, A.J. Tebben, K.A. Lentz, J.E. Grace, J.A. Marcinkeviciene, L.M. Kopcho, C.R. Burton, D.M. Barten, J.H. Toyn, J.E. Meredith, C.F. Albright, J.J. Bronson, J.E. Macor, and L.A. Thompson. 2011. Synthesis and SAR of indole- and 7-azaindole-1,3-dicarboxamide hydroxyethylamine inhibitors of BACE-1. Bioorganic and Medicinal Chemistry Letters 21: 537–541.

    Article  CAS  Google Scholar 

  • Menta, E., Pescalli, N. 2004. U. S. Patent 6753342.

  • Pavan, F.R., P.I.D.S. Maia, S.R.A. Leite, V.M. Deflon, A.A. Batista, D.N. Sato, S.G. Franzblau, and C.Q.F. Leite. 2010. Thiosemicarbazones, semicarbazones, dithiocarbazates and hydrazide/hydrazones: anti-Mycobacterium tuberculosis activity and cytotoxicity. European Journal of Medicinal Chemistry 45: 1898–1905.

    Article  CAS  Google Scholar 

  • Penthala, N.R., T.R. Yerramreddy, and P.A. Crooks. 2011. Synthesis and in vitro screening of novel N-benzyl aplysinopsin analogs as potential anticancer agents. Bioorganic and Medicinal Chemistry Letters 21: 1411–1413.

    Article  CAS  Google Scholar 

  • Pintori, D.G., and M.F. Greaney. 2011. Intramolecular Oxidative C–H Coupling for Medium-Ring Synthesis. Journal of the American Chemical Society 133: 1209–1211.

    Article  CAS  Google Scholar 

  • Reddy, Y.T., K.R. Sekhar, N. Sasi, P.N. Reddy, M.L. Freeman, and P.A. Crooks. 2010. Novel substituted (Z)-5-((N-benzyl-1H-indol-3-yl)methylene)imidazolidine-2,4-diones and 5-((N-benzyl-1H-indol-3-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones as potent radio-sensitizing agents. Bioorganic and Medicinal Chemistry Letters 20: 600–602.

    Article  CAS  Google Scholar 

  • Rezayan, A.H., P. Azerang, S. Sardari, and A. Sarvary. 2012. Synthesis and biological evaluation of coumarin derivatives as inhibitors of Mycobacterium bovis (BCG). Chemical Biology and Drug Design 80: 929–936.

    Article  CAS  Google Scholar 

  • Shahab, F.M., F. Kobarfard, and S. Dadashzadeh. 2009. Simultaneous determination of a new antituberculosis agent KBF-611 and its de-acetylated metabolite in mouse and rabbit plasma by HPLC. Archives of Pharmacal Research 32: 1453–1460.

    Article  CAS  Google Scholar 

  • Singh, P., M. Kaur, and P. Verma. 2009. Design, synthesis and anticancer activities of hybrids of indole and barbituric acids—Identification of highly promising leads. Bioorganic and Medicinal Chemistry Letters 19: 3054–3058.

    Article  CAS  Google Scholar 

  • Sriram, D., P. Yogeeswari, R. Thirumurugan, and R.K. Pavana. 2006. Discovery of new antitubercular oxazolyl thiosemicarbazones. Journal of Medicinal Chemistry 49: 3448–3450.

    Article  CAS  Google Scholar 

  • Sriram, D., P. Yogeeswari, P. Dhakla, P. Senthilkumar, and D. Banerjee. 2007. N-Hydroxythiosemicarbazones: Synthesis and in vitro antitubercular activity. Bioorganic and Medicinal Chemistry Letters 17: 1888–1891.

    Article  CAS  Google Scholar 

  • Sriram, D., P. Yogeeswari, P. Dhakla, P. Senthilkumar, D. Banerjee, and T. Manjashetty. 2009. H., 5-Nitrofuran-2-yl derivatives: Synthesis and inhibitory activities against growing and dormant mycobacterium species. Bioorganic and Medicinal Chemistry Letters 19: 1152–1154.

    Article  CAS  Google Scholar 

  • Tholander, J., and J. Bergman. 1999. Syntheses of 6-substituted indolo[3,2-b]carbazoles, including 6-formylindolo[3,2-b]carbazole, an extremely efficient ligand for the TCDD (Ah) receptor. Tetrahedron 55: 6243–6260.

    Article  CAS  Google Scholar 

  • Umamatheswari, S., B. Balaji, M. Ramanathan, and S. Kabilan. 2011. Synthesis, stereochemistry, antimicrobial evaluation and QSAR studies of 2,6-diaryltetrahydropyran-4-one thiosemicarbazones. European Journal of Medicinal Chemistry 46: 1415–1424.

    Article  CAS  Google Scholar 

  • Voelker, T., T. Ewell, J. Joo, and E.D. Edstrom. 1998. o-Nitrobenzyl as a photocleavable nitrogen protecting group for indoles, benzimidazole, and 6-chlorouracil. Tetrahedron Letters 39: 359–362.

    Article  CAS  Google Scholar 

  • Weller, L.E., H.M. Sell, and R.Y. Gottshall. 1954. 3-Indolecarboxaldehyde thiosemicarbazone, a new antitubercular compound. Journal of the American Chemical Society 76: 1959.

    Article  CAS  Google Scholar 

  • Wu, S., L. Wang, W. Guo, X. Liu, J. Liu, X. Wei, and B. Fang. 2011. Analogues and derivatives of oncrasin-1, a novel inhibitor of the C-terminal domain of RNA polymerase II and their antitumor activities. Journal of Medicinal Chemistry 54: 2668–2679.

    Article  CAS  Google Scholar 

  • Yu, Y., D.S. Kalinowski, Z. Kovacevic, A.R. Siafakas, P.J. Jansson, C. Stefani, D.B. Lovejoy, P.C. Sharpe, P.V. Bernhardt, and D.R. Richardson. 2009. Thiosemicarbazones from the old to new: Iron chelators that are more than just ribonucleotide reductase inhibitors. Journal of Medicinal Chemistry 52: 5271–5294.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Dr. Maryam Nakhjavani for her helpful suggestions in the cytotoxicity evaluation of the synthesized derivatives.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Biotechnology, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran

    Vida Mashayekhi

  2. Department of Medicinal Chemistry, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran

    Kamaleddin Haj Mohammad Ebrahim Tehrani

  3. Drug Design and Bioinformatics Unit, Department of Medical Biotechnology, Biotechnology Research Center, Pasteur Institute, 13164, Tehran, Iran

    Parisa Azerang & Soroush Sardari

  4. Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Vali Asr Ave., Niayesh Junction, P.O. Box 14155-6153, Tehran, Iran

    Farzad Kobarfard

  5. Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Farzad Kobarfard

Authors
  1. Vida Mashayekhi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kamaleddin Haj Mohammad Ebrahim Tehrani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Parisa Azerang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Soroush Sardari
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Farzad Kobarfard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Farzad Kobarfard.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mashayekhi, V., Haj Mohammad Ebrahim Tehrani, K., Azerang, P. et al. Synthesis, antimycobacterial and anticancer activity of novel indole-based thiosemicarbazones. Arch. Pharm. Res. 44, 1–13 (2021). https://doi.org/10.1007/s12272-013-0242-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-013-0242-z

Keywords

Search

Navigation