Chemistry of Heterocyclic Compounds

, Volume 50, Issue 10, pp 1432–1443 | Cite as

Synthesis and Evaluation of Reducing Capacity and Calcium Channel Blocking Activity of Novel 3,5-Dipropargylcarbonyl-Substituted 1,4-Dihydropyridines*

  • M. Rucins
  • M. Gosteva
  • I. Domracheva
  • I. Kanepe-Lapsa
  • S. Belyakov
  • M. Plotniece
  • K. Pajuste
  • B. Cekavicus
  • M. Jekabsone
  • A. Sobolev
  • I. Shestakova
  • А. PlotnieceEmail author

Novel pyridinium salts based on 4-(3-pyridyl)-3,5-dipropargylcarbonyl-1,4-dihydropyridine were obtained by quaternization of pyridine moiety with different alkyl halides. The reducing capacity of the synthesized compounds was evaluated using the phosphomolybdenum complex method. The obtained results confirmed that all tested compounds possessed reducing capacity. Ca2+ channel antagonist and agonist activities of the compounds were additionaly assayed by changes in intracellular Ca2+ ion concentration in H9C2 and A7R5 cell lines. The obtained data confirmed that all synthesized 1,4-dihydropyridine derivatives have smooth muscle selective antagonist activities, and in the case of 4-phenyl derivative the activity was 4.7 times higher than that of amlodipine.


N-alkyl pyridinium 1,4-dihydropyridines calcium antagonists Hantzsch synthesis quaternization reducing capacity 


This research work was supported by the European Social Fund Project No. ESF 2013/0002/1DP/ and the European Social Fund within the project “Support for Doctoral Studies at University of Latvia” (for Martins Rucins).

We are also grateful to Dr. Ilga Mutule for assistance in the work with MW equipment and B.Sc. Katrina Veinberga for technical assistance.


  1. 1.
    E. Carosati, P. Ioan, M. Micucci, F. Broccatelli, G. Cruciani, B. S. Zhorov, A. Chiarini, and R. Budriesi, Curr. Med. Chem., 19, 4306 (2012).CrossRefGoogle Scholar
  2. 2.
    P. Ioan, E. Carosati, M. Micucci, G. Cruciani, F. Broccatelli, B. S. Zhorov, A. Chiarini, and R. Budriesi, Curr. Med. Chem., 18, 4901 (2011).CrossRefGoogle Scholar
  3. 3.
    D. J. Triggle, Biochem. Pharmacol., 78, 217 (2009).CrossRefGoogle Scholar
  4. 4.
    D. J. Triggle, Biochem. Pharmacol., 74, 1 (2007).CrossRefGoogle Scholar
  5. 5.
    D. J. Triggle, Mini-Rev. Med. Chem., 3, 215 (2003).CrossRefGoogle Scholar
  6. 6.
    N. Edraki, A. R. Mehdipour, M. Khoshneviszadeh, and R. Miri, Drug Discovery Today, 14, 1058 (2009).CrossRefGoogle Scholar
  7. 7.
    G. Duburs, B. Vīgante, A. Plotniece, A. Krauze, A. Sobolevs, J. Briede, V. Kluša, and A. Velēna, Chim. Oggi, 26, 68 (2008).Google Scholar
  8. 8.
    S. Nobili, I. Landini, B. Giglioni, and E. Mini, Curr. Drug Targets, 7, 861 (2006).CrossRefGoogle Scholar
  9. 9.
    A. R. Mehdipour, K. Javidnia, B. Hemmateenejad, Z. Amirghofran, and R. Miri, Chem. Biol. Drug Des., 70, 337 (2007).CrossRefGoogle Scholar
  10. 10.
    B. Voigt, C. Coburger, J. Monár, and A. Hilgeroth, Bioorg. Med. Chem., 15, 5110 (2007).CrossRefGoogle Scholar
  11. 11.
    M. I. Szabon-Watola, S. V. Ulatowski, K. M. George, C. D. Hayes, S. A. Steiger, and N. R. Natale, Bioorg. Med. Chem. Lett., 24, 117 (2014).CrossRefGoogle Scholar
  12. 12.
    G. D. Tirzit, I. M. Byteva, K. I. Salokhiddinov, G. P. Gurinovich, and G. Y. Dubur, Chem. Heterocycl. Compd., 17, 682 (1981). [Khim. Geterotsikl. Soedin., 924 (1981).]CrossRefGoogle Scholar
  13. 13.
    A. Augustyniak, G. Bartosz, A. Čipak, G. Duburs, L. Horáková, W. Łuczaj, M. Majekova, A. D. Odysseos, L. Rackova, E. Skrzydlewska, M. Stefek, M. Strosova, G. Tirzitis, P. R. Venskutonis, J. Viskupicova, P. S. Vraka, and N. Zarkovic, Free Radical Res., 44, 1216 (2010).CrossRefGoogle Scholar
  14. 14.
    R. Miri, K. Javidnia, H. Mirkhani, F. Kazemi, B. Hemmateenejad, N. Edraki, and A. R. Mehdipour, Daru, J. Pharm. Sci., 16, 263 (2008).Google Scholar
  15. 15.
    W. A. Catterall and J. Striessnig, Trends Pharmacol. Sci., 13, 256 (1992).CrossRefGoogle Scholar
  16. 16.
    C. Becker, S. S. Jick, and C. R. Meier, Neurology, 70, 1438 (2008).CrossRefGoogle Scholar
  17. 17.
    B. Ritz, S. L. Rhodes, L. Qian, E. Schernhammer, J. H. Olsen, and S. Friis, Ann. Neurol., 67, 600 (2010).Google Scholar
  18. 18.
    O. Weinreb, T. Amit, O. Bar-Am, and M. B. Youdim, Prog. Neurobiol., 92, 330 (2010).CrossRefGoogle Scholar
  19. 19.
    Y. Bansal and O. Silakari, Eur. J. Med. Chem., 76, 31 (2014).CrossRefGoogle Scholar
  20. 20.
    D. Tirzite, J. Koronova, and A. Plotniece, Biochem. Mol. Biol. Int., 45, 849 (1998).Google Scholar
  21. 21.
    M. Rucins, D. Kaldre, K. Pajuste, M. A. S. Fernandes, J. A. F. Vicente, L. Klimaviciusa, E. Jaschenko, I. Kanepe-Lapsa, I. Shestakova, M. Plotniece, M. Gosteva, A. Sobolev, B. Jansone, R. Muceniece, V. Klusa, and A. Plotniece, C. R. Chim., 17, 69 (2014).CrossRefGoogle Scholar
  22. 22.
    P. Cruciani, R. Stammler, C. Aubert, and M. Malacria, J. Org. Chem., 61, 2699 (1996).CrossRefGoogle Scholar
  23. 23.
    A. Hantzsch, Justus Liebigs Ann. Chem., 215, 1 (1882).CrossRefGoogle Scholar
  24. 24.
    E. E. Liepinsh, R. M. Zolotoyabko, B. S. Chekavichus, A. E. Sausin’, V. K. Lusis, and G. Ya. Dubur, Chem. Heterocycl. Compd., 25, 1032 (1989). [Khim. Geterotsikl. Soedin., 1232 (1989).]CrossRefGoogle Scholar
  25. 25.
    S. Goldmann and J. Stoltefuss, Angew. Chem., Int. Ed., 30, 1559 (1991).CrossRefGoogle Scholar
  26. 26.
    J. Kuthan and A. Kurfurst, Ind. Eng. Chem. Prod. Res. Dev., 21, 191 (1982).CrossRefGoogle Scholar
  27. 27.
    A. Altomare, M. Burla, M. Camalli, G. Cascarano, C. Giacovazzo, A. Guagliardi, A. G. G. Moliterni, and R. Spagna, Appl. Cryst., 32, 115 (1999).CrossRefGoogle Scholar
  28. 28.
    S. Mackay, W. Dong, C. Edwards, A. Henderson, C. J. Gilmore, N. Stewart, K. Shankland, and A. Donald, maXus: Integrated Crystallography Software, Bruker-Nonius and University of Glasgow, 2003.Google Scholar
  29. 29.
    D. Pijper, E. Bulten, J. Šmisterová, A. Wagenaar, D. Hoekstra, J. B. F. N. Engberts, and R. Hulst, Eur. J. Org. Chem., 2003, 4406 (2003).CrossRefGoogle Scholar
  30. 30.
    N. V. Makarova, A. Plotnietse, G. Tirzitis, I. Turovskii, and G. Dubur, Chem. Heterocycl. Compd., 33, 175 (1997). [Khim. Geterotsikl. Soedin., 202 (1997).]CrossRefGoogle Scholar
  31. 31.
    F. P. Guengerich, W. R. Brian, M. Iwasaki, M. A. Sari, C. Bäärnhielm, and P. Berntsson, J. Med. Chem., 34, 1838 (1991).CrossRefGoogle Scholar
  32. 32.
    G. D. Tirzit and G. Ya. Dubur, Chem. Heterocycl. Compd., 8, 126 (1972). [Khim. Geterotsikl. Soedin., 133 (1972).]CrossRefGoogle Scholar
  33. 33.
    D. Ya. Tirzite, Zh. V. Khyuvonen, A. G. Shmidlers, G. D. Tirzitis, and G. Ya. Duburs, Pharm. Chem. J., 34, 297 (2000). [Khim.-Farm. Zh., 34, № 6, 17 (2000).]CrossRefGoogle Scholar
  34. 34.
    P. Prieto, M. Pineda, and M. Aguilar, Anal. Biochem., 269, 337 (1999).CrossRefGoogle Scholar
  35. 35.
    L. Kouřimská, J. Pokorný, and G. Tirzitis, Nahrung, 37, 91 (1993).CrossRefGoogle Scholar
  36. 36.
    R. W. Hadley and J. R. Hume, Circ. Res., 62, 97 (1988).CrossRefGoogle Scholar
  37. 37.
    M. Rucins, M. Gosteva, S. Belyakov, A. Sobolev, K. Pajuste, M. Plotniece, B. Cekavicus, D. Tirzite, and A. Plotniece, Aust. J. Chem., DOI:  10.1071/CH14033 (2014).Google Scholar
  38. 38.
    E. Pretsch, W. Simon, J. Seibl, and T. Clerc, in: W. Fresenius, J. F. K. Huber, E. Pungor, G. A. Rechnitz, W. Simon, and Th. S. West (editors), Tables of Spectal Data for Structure Determination of Organic Compounds, Springer-Verlag, Berlin, Heidelberg (1989).CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • M. Rucins
    • 1
    • 2
  • M. Gosteva
    • 1
  • I. Domracheva
    • 1
  • I. Kanepe-Lapsa
    • 1
  • S. Belyakov
    • 1
  • M. Plotniece
    • 1
  • K. Pajuste
    • 1
  • B. Cekavicus
    • 1
  • M. Jekabsone
    • 2
  • A. Sobolev
    • 1
  • I. Shestakova
    • 1
  • А. Plotniece
    • 1
    Email author
  1. 1.Latvian Institute of Organic SynthesisRigaLatvia
  2. 2.Faculty of MedicineUniversity of LatviaRigaLatvia

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