Skip to main content
SpringerLink
Log in

Design, synthesis and antiproliferative activity of new amine, amino acid and dipeptide-coupled benzamides as potential sigma-1 receptor

  • Original Paper
  • Published:
Journal of the Iranian Chemical Society Aims and scope Submit manuscript

Abstract

N-Alkyl-2-(substitutedbenzamido) benzamides and methyl 2-(2-(substitutedbenzamido) benzamido) alkanoates were prepared by either the reaction of amines or amino acid esters with benzoxazine derivatives or the DCC coupling of 2-substitutedbenzamido benzoic acid with amines or amino acid esters. Methyl 2-(2-(4-chlorobenzamido)benzamido alkanoates were used as the key intermediate for the preparation of dipeptide-coupled benzamides via azide and DCC coupling methods. The investigated compounds were subjected to in silico molecular docking as agonist for human σ1 receptor through their binding energies and analysis of ligand–receptor interactions and prediction study to their physicochemical properties and drug-likeness scores. Moreover, compounds with the highest binding affinity toward the target were screened against breast MCF-7 and liver A549 cancer cell lines to test their cytotoxic activities. Compounds 11a, 3a, 8c, 12a and 13b showed potent cytotoxic activity for the tested compounds against MCF-7 cell line with low IC50 values, especially for 11a (5.3 µM compared to the standard drug 5-FU 5.8 µM). Based on the identification of this hit candidate, new potent σ1 receptor with anti-cancer activity could be designed.

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

Scheme 1
Scheme 2
Fig. 1
Scheme 3
Scheme 4
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. F. Bray, J. Ferlay, I. Soerjomataram, R.L. Siegel, L.A. Torre, A. Jemal, CA Cancer J. Clin. 68, 394 (2018)

    Google Scholar 

  2. S. BW, W. CP, World Cancer Report 2014 (2014)

  3. R. Moreno-Sánchez, A. Marín-Hernández, E. Saavedra, J.P. Pardo, S.J. Ralph, S. Rodríguez-Enríquez, Int. J. Biochem. Cell Biol. 50, 10 (2014)

    PubMed  Google Scholar 

  4. S.B. Hellewell, A. Bruce, G. Feinstein, J. Orringer, W. Williams, W.D. Bowen, Eur. J. Pharmacol. 268, 9 (1994)

    CAS  PubMed  Google Scholar 

  5. R. Quirion, W.D. Bowen, Y. Itzhak, J.L. Junien, J.M. Musacchio, R.B. Rothman, S. Tsung-Ping, S.W. Tam, D.P. Taylor, Trends Pharmacol. Sci. 13, 85 (1992)

    CAS  PubMed  Google Scholar 

  6. M. Hanner, F.F. Moebius, A. Flandorfer, H.G. Knaus, J. Striessnig, E. Kempner, H. Glossmann, Proc. Natl. Acad. Sci. USA 93, 8072 (1996)

    CAS  PubMed  Google Scholar 

  7. W.D. Bowen, in Pharmacochemistry Library, edited by U. Gulini, M. Gianella, W. Quaglia, G. Marucci (Elsevier, 2000), pp. 211–218

  8. B.J. Vilner, C.S. John, W.D. Bowen, Cancer Res. 55, 408 (1995)

    CAS  PubMed  Google Scholar 

  9. E. Aydar, C.P. Palmer, M.B.A. Djamgoz, Cancer Res. 64, 5029 (2004)

    CAS  PubMed  Google Scholar 

  10. J.E. Bermack, G. Debonnel, Br. J. Pharmacol. 134, 691 (2001)

    CAS  PubMed  PubMed Central  Google Scholar 

  11. C.S. John, W.D. Bowen, S.J. Fisher, B.B. Lim, B.C. Geyer, B.J. Vilner, R.L. Wahl, Nucl. Med. Biol. 26, 377 (1999)

    CAS  PubMed  Google Scholar 

  12. B. Bourrie, E. Bribes, J.-M. Derocq, H. Vidal, P. Casellas, Curr. Opin. Investig. Drugs 5, 1158 (2004)

    CAS  PubMed  Google Scholar 

  13. P. Brent, G. Pang, Eur. J. Pharmacol. 278, 151 (1995)

    CAS  PubMed  Google Scholar 

  14. B.J. Vilner, B.R. deCosta, W.D. Bowen, J. Neurosci. Off. J. Soc. Neurosci. 15, 117 (1995)

    CAS  Google Scholar 

  15. P. Brent, G. Pang, G. Little, P. Dosen, D. Van Helden, Biochem. Biophys. Res. Commun. 219, 219 (1996)

    CAS  PubMed  Google Scholar 

  16. T. Moody, J. Leyton, C. John, Life Sci. 66, 1979 (2000)

    CAS  PubMed  Google Scholar 

  17. B.A. Spruce, L.A. Campbell, N. McTavish, M.A. Cooper, M.V.L. Appleyard, M. O’Neill, J. Howie, J. Samson, S. Watt, K. Murray, D. McLean, N.R. Leslie, S.T. Safrany, M.J. Ferguson, J.A. Peters, A.R. Prescott, G. Box, A. Hayes, B. Nutley, F. Raynaud, C.P. Downes, J.J. Lambert, A.M. Thompson, S. Eccles, Cancer Res. 64, 4875 (2004)

    CAS  PubMed  Google Scholar 

  18. K.W. Crawford, A. Coop, W.D. Bowen, Eur. J. Pharmacol. 443, 207 (2002)

    CAS  PubMed  Google Scholar 

  19. S. Elmore, Toxicol. Pathol. 35, 495 (2007)

    CAS  PubMed  PubMed Central  Google Scholar 

  20. M. Aboul-Enein, A. El-Azzouny, Y. Maklad, F. Ragab, M. Abdel-Maksoud, Egyptian. Pharm. J. 13, 1 (2014)

    Google Scholar 

  21. D. Mussoi, G. Boswell, N. Mehta, F. Soroko, C. Burchall, Eur. J. Med. Chem. 31, 331 (1996)

    Google Scholar 

  22. A. Kumar, B. Narasimhan, D. Kumar, Bioorg. Med. Chem. 15, 4113 (2007)

    CAS  PubMed  Google Scholar 

  23. B. Narayana, K.K. VijayaRaj, B.V. Ashalatha, N.S. Kumari, B.K. Sarojini, Eur. J. Med. Chem. 39, 867 (2004)

    CAS  PubMed  Google Scholar 

  24. G. Caliendo, V. Santagada, E. Perissutti, B. Severino, F. Fiorino, T.D. Warner, J.L. Wallace, D.R. Ifa, E. Antunes, G. Cirino, G. de Nucci, Eur. J. Med. Chem. 36, 517 (2001)

    CAS  PubMed  Google Scholar 

  25. N. Charaya, D. Pandita, A.S. Grewal, V. Lather, Comput. Biol. Chem. 73, 221 (2018)

    CAS  PubMed  Google Scholar 

  26. N.A. Gujarati, L. Zeng, P. Gupta, Z.-S. Chen, V.L. Korlipara, Bioorg. Med. Chem. Lett. 27, 4698 (2017)

    CAS  PubMed  Google Scholar 

  27. M. Schlitzer, I. Sattler, A. Friese, I. Zündorf, T. Dingermann, Anticancer Res. 20, 1723 (2000)

    CAS  PubMed  Google Scholar 

  28. J. Jiao, H. Fang, X. Wang, P. Guan, Y. Yuan, W. Xu, Eur. J. Med. Chem. 44, 4470 (2009)

    CAS  PubMed  Google Scholar 

  29. A. Lu, H. Luo, M. Shi, G. Wu, Y. Yuan, J. Liu, F. Tang, Bioorg. Med. Chem. Lett. 21, 4924 (2011)

    CAS  PubMed  Google Scholar 

  30. S. Nara, A. Garlapati, Ars Pharmaceutica (Internet) 59, 121 (2018)

    Google Scholar 

  31. M. Megahed, W. Fathalla, A.A. Alsheikh, J. Heterocycl. Chem. 55, 2799 (2018)

    CAS  Google Scholar 

  32. G.W. Anderson, J.E. Zimmerman, F.M. Callahan, J. Am. Chem. Soc. 86, 1839 (1964)

    CAS  Google Scholar 

  33. A.M. Alafeefy, A.A. Kadi, O.A. Al-Deeb, K.E.H. El-Tahir, N.A. Al-jaber, Eur. J. Med. Chem. 45, 4947 (2010)

    CAS  PubMed  Google Scholar 

  34. A.S. El-Azab, M.A. Al-Omar, A.A.-M. Abdel-Aziz, N.I. Abdel-Aziz, M.A.-A. El-Sayed, A.M. Aleisa, M.M. Sayed-Ahmed, S.G. Abdel-Hamide, Eur. J. Med. Chem. 45, 4188 (2010)

    CAS  PubMed  Google Scholar 

  35. M.R. Yadav, S.T. Shirude, A. Parmar, R. Balaraman, R. Giridhar, Chem. Heterocycl. Compd. 42, 1038 (2006)

    CAS  Google Scholar 

  36. V. Mittapelli, Der Pharma Chemica 6, 272 (2014)

    CAS  Google Scholar 

  37. S.M. El Rayes, I.A.I. Ali, W. Fathalla, Arkivoc 2008, 86 (2008)

    Google Scholar 

  38. E.F. Ismail, I.A.I. Ali, W. Fathalla, A.A. Alsheikh, E.S.E. Tamneya, Arkivoc 2017, 104 (2017)

    Google Scholar 

  39. C.A. Lipinski, F. Lombardo, B.W. Dominy, P.J. Feeney, Adv. Drug Deliv. Rev. 46, 3 (2001)

    CAS  PubMed  Google Scholar 

  40. C.A. Lipinski, Drug Discovery Today: Technologies 1, 337 (2004)

    CAS  PubMed  Google Scholar 

  41. P.D. Leeson, B. Springthorpe, Nat. Rev. Drug Discov. 6, 881 (2007)

    CAS  PubMed  Google Scholar 

  42. D.E. Clark, S.D. Pickett, Drug Discovery Today 5, 49 (2000)

    CAS  PubMed  Google Scholar 

  43. A.K. Ghose, T. Herbertz, R.L. Hudkins, B.D. Dorsey, J.P. Mallamo, A.C.S. Chem, Neuroscience 3, 50 (2012)

    CAS  Google Scholar 

  44. D.F. Veber, S.R. Johnson, H.-Y. Cheng, B.R. Smith, K.W. Ward, K.D. Kopple, J. Med. Chem. 45, 2615 (2002)

    CAS  Google Scholar 

  45. M.S. Nafie, M.A. Tantawy, G.A. Elmgeed, Steroids 152, 108485 (2019)

    CAS  PubMed  Google Scholar 

  46. H.R. Schmidt, S. Zheng, E. Gurpinar, A. Koehl, A. Manglik, A.C. Kruse, Nature 532, 527 (2016)

    CAS  PubMed  PubMed Central  Google Scholar 

  47. A.I. Khodair, M.A. Alsafi, M.S. Nafie, Carbohyd. Res. 486, 107832 (2019)

    Google Scholar 

  48. M.G. Salem, Y.M.A. Aziz, M. Elewa, H.A. Elshihawy, M.M. Said, Bioorg. Med. Chem. 27, 3383 (2019)

    CAS  PubMed  Google Scholar 

  49. A. Daina, O. Michielin, V. Zoete, Sci. Rep. 7, 42717 (2017)

    PubMed  PubMed Central  Google Scholar 

  50. T. Mosmann, J. Immunol. Methods 65, 55 (1983)

    CAS  Google Scholar 

  51. R. Ian, Freshney, Culture of Animal Cells: A Manual of Basic Technique and Specialized Applications (Wiley-Blackwell, Hoboken, 2010)

    Google Scholar 

Download references

Funding

This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Physics and Math. Engineering Department, Faculty of Engineering, Port-Said University, Port Said, Egypt

    Eman Youssef & Walid Fathalla

  2. Chemistry Department, Faculty of Science, Port-Said University, Port Said, Egypt

    Mohamed Abd El-Moneim

  3. Chemistry Department, Faculty of Science, Suez Canal University, Ismailia, 41522, Egypt

    Mohamed S. Nafie

Authors
  1. Eman Youssef
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mohamed Abd El-Moneim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Walid Fathalla
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mohamed S. Nafie
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

EY synthesized the entire series of new amine, amino acid and dipeptide-coupled benzamide derivatives under main supervision of WF and MAEM, who designed the idea and supervised the synthesis and characterization part. MSN initiated the idea and design of the biology part by carrying out in silico molecular docking and bioinformatics, cytotoxic screening. All authors contributed to data analysis and manuscript writing in their corresponding parts. MSN carried out the linguistic revision for the whole manuscript and validated it in the final submitted form, and additionally, he followed up the publication process from submission through the review to acceptance.

Corresponding authors

Correspondence to Walid Fathalla or Mohamed S. Nafie.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

13738_2020_1947_MOESM1_ESM.rar

The bioinformatics data of the investigated compounds together with spectroscopic characterization charts, some biological activity data are provided as supporting information online (RAR 11530 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Youssef, E., El-Moneim, M.A., Fathalla, W. et al. Design, synthesis and antiproliferative activity of new amine, amino acid and dipeptide-coupled benzamides as potential sigma-1 receptor. J IRAN CHEM SOC 17, 2515–2532 (2020). https://doi.org/10.1007/s13738-020-01947-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13738-020-01947-6

Keywords

Search

Navigation