Skip to main content

Synthesis and Bio-Evaluation of N-Benzylpiperidine-8-Hydroxyquinoline Derivatives as Potential Cholinesterase Inhibitors, Metal Ion Chelators and Calcium Channel Blockers

Abstract

A new series of N-benzylpiperidine 8-hydroxyquinoline derivatives were synthesized and evaluated as cholinesterase inhibitors, metal ion chelators and calcium channel blockers. It was found that the ethyl cholinesterase inhibition activity could be improved when the linker between N-benzylpiperidine and 8‑hydroxyquinoline groups were extended. Among all derivatives, compound (XIIId) showed best acetyl cholinesterase inhibition activity with an IC50 value of 0.24 ± 0.03 μM. It also showed metal ion chelating activity with a metal-compound ratio of 1 : 2 on copper or zinc ions. The calcium channel blocking property of select compounds were tested and compared by patching clamp on HEK293 cell expressing Cav1.2 calcium channel. Among tested compounds, cholinesterase inhibitor 8c showed mild calcium channel blockade activity with the inhibition ratio of calcium channel of 24.56 ± 2.44% (10 μM). This result suggested that the potential neuroprotective ability of this cholinesterase inhibitor might be partially related to the calcium channel blocking property.

This is a preview of subscription content, access via your institution.

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.

REFERENCES

  1. Lester, H. A., Sci. Am., 1977, vol. 236, pp. 106–116.

    CAS  Article  Google Scholar 

  2. Li, Q., He, S., Chen, Y., Feng, F., Qu, W., and Sun, H., Eur. J. Med. Chem. 2018, vol. 158, pp. 463–477. https://doi.org/10.1016/j.ejmech.2018.09.031

    CAS  Article  PubMed  Google Scholar 

  3. Taylor, P., In: Gilman, A. G., Rall, T. W., Nies, A. S., and Taylor, P., The Pharmacologial Basis of Therapeutics, New York: Pergamon, 1990, pp. 131–136.

    Google Scholar 

  4. Yu, Q., Holloway, H.W., Utsuki, T., Brossi, A., and Greig, N.H., J. Med. Chem. 1999, vol. 42, pp. 1855–1861. https://doi.org/10.1021/jm980459s

    CAS  Article  PubMed  Google Scholar 

  5. Bajda, M., Guzior, N., Ignasik, M., and Malawska, B., Curr. Med. Chem. 2011, vol. 18, pp. 4949–4975. https://doi.org/10.2174/092986711797535245

    CAS  Article  PubMed  Google Scholar 

  6. Oset-Gasque, M. J. and Marco-Contelles, J., ACS Chem. Neurosci. 2018, vol. 9, pp. 401–403. https://doi.org/10.1021/acschemneuro.8b00069

    CAS  Article  PubMed  Google Scholar 

  7. Lanthier, C., Payan, H., Liparulo, I., Hatat, B., Lecoutey, C., Since, M., Davis, A., Bergamini, C., Claeysen, S., Dallemagne, P., Bolognesi, M. L., and Rochais, C., Eur. J. Med. Chem., 2019, vol. 182, e111596. https://doi.org/10.1016/j.ejmech.2019.111596

    CAS  Article  Google Scholar 

  8. Corona, C., Pensalfini, A., Frazzini, V., and Sensi, S.L., Cell Death Dis., 2011, vol. 2, e176. https://doi.org/10.1038/cddis.2011.57

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. McGeer, P. L., Rogers, J., and McGeer, E. G., J. Alzheimers Dis., 2016, vol. 54, pp. 853–857. https://doi.org/10.3233/JAD-160488

    Article  PubMed  Google Scholar 

  10. Pchitskaya, E., Popugaeva, E., and Bezprozvanny, I., Cell Calcium., 2018, vol. 70, pp. 87–94. https://doi.org/10.1016/j.ceca.2017.06.008

    CAS  Article  PubMed  Google Scholar 

  11. Chakroborty, S., Briggs, C., Miller, M. B., Goussakov, I., Schneider, C., Kim, J., Wicks, J., Richardson, J.C., Conklin, V., and Cameransi, B. G., PLoS One, 2012, vol. 7. e52056. https://doi.org/10.1371/journal.pone.0052056

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Hopp, S.C., D’Angelo, H.M., Royer, S.E., Kaercher, R.M., Crockett, A.M., Adzovic, L., and Wenk, G.L., Neuroinflammation., 2015, vol. 12, pp. 56–69. https://doi.org/10.1186/s12974-015-0262-3

    CAS  Article  Google Scholar 

  13. Hopp, S. C., D’Angelo, H. M., Royer, S. E., Kaercher, R.M., Adzovic, L., and Wenk, G. L., Neuroscience., 2014, vol. 280, pp. 10–18. https://doi.org/10.1016/j.neuroscience.2014.09.007

    CAS  Article  PubMed  Google Scholar 

  14. Marco-Contelles, J., León, R, de los Ríos, C., Samadi, A., Bartolini, M., Andrisano, V., Huertas, O., Barril, X., Luque, F. J., and Rodríguez-Franco, M. I., J. Med. Chem., 2009, vol. 52, pp. 2724–2732. https://doi.org/10.1021/jm801292b

    CAS  Article  PubMed  Google Scholar 

  15. Solntseva, E. I., Bukanova, J. V., Marchenko, E., and Skrebitsky, V. G., Comp. Biochem. Physiol. C., 2007, vol. 144, pp. 319–326. https://doi.org/10.1016/j.cbpc.2006.10.001

    CAS  Article  Google Scholar 

  16. Wang, L., Esteban, G., Ojima, M., Bautista-Aguilera, O.M., Inokuchi, T., Moraleda, I., Iriepa, I., Samadi, A., Youdim, M. B.H., and Romero, A., Eur. J. Med Chem., 2014, vol. 80, pp. 543–561. https://doi.org/10.1016/j.ejmech.2014.04.078

    CAS  Article  PubMed  Google Scholar 

  17. Du, D. M. and Carlier, P. R., Curr. Pharm. Des., 2004, vol. 10, pp. 3141–3156. https://doi.org/10.2174/1381612043383412

    CAS  Article  PubMed  Google Scholar 

  18. Muñoz-Torrero, D. and Camps, P., Curr. Med. Chem., 2006, vol. 13, pp. 399–422. https://doi.org/10.2174/092986706775527974

    Article  PubMed  Google Scholar 

  19. Pang, Y. P., Quiram, P., Jelacic, T., Hong, F. and Brimijoin, S., J. Biol. Chem., 1996, vol. 271, pp. 23646–23649.

    CAS  Article  Google Scholar 

  20. Wang, L., Moraleda, I., Iriepa, I., Romero, A., López-Muñoz, F., Chioua, M., Inokuchi, T., Bartolini, M., and Marco-Contelles, J., Med. Chem. Commun., 2017, vol. 8, pp. 1307–1317. https://doi.org/10.1039/C7MD00143F

    CAS  Article  Google Scholar 

  21. Wu, M. Y., Esteban, G., Brogi, S., Shionoya, M., Wang, L., Campiani, G., Unzeta, M., Inokuchi, T., Butini, S., and Marco-Contelles, J., Eur. J. Med. Chem., 2016, vol. 121, pp. 864–879. https://doi.org/10.1016/j.ejmech.2015.10.001

    CAS  Article  PubMed  Google Scholar 

  22. Ellman, G. L., Courtney, K. D., Andres, V., and Featherstone, R. M., Biochem. Pharmacol., 1961, vol. 7, pp. 88–95.

    CAS  Article  Google Scholar 

  23. Wang, Z., Sun, H., Yao, X., Li, D., Xu, L., Li, Y., Tian, S., and Hou, T., Phys. Chem. Chem. Phys., 2016, vol. 18, pp. 12964–12975. https://doi.org/10.1039/c6cp01555g

    CAS  Article  PubMed  Google Scholar 

  24. Huang, X., Cuanjungco, M.P., Atwood, C.S., Hartshorn, M.A., Tyndall, J.D., Hanson, G.R., Stokes, K.C., Leopold, M., Multhaup, G., and Goldstein, L.E., J. Biol. Chem., 1999, vol. 274, pp. 37111–37116. https://doi.org/10.1074/jbc.274.52.37111

    CAS  Article  PubMed  Google Scholar 

  25. Hane, F. and Leonenko, Z., Biomolecules, 2014, vol. 4, pp. 101–116. https://doi.org/10.3390/biom4010101

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Anekonda, T.S., Quinn, J.F., Harris, C., Frahler, K., Wadsworth, T. L., and Woltjer, R. L., Neurobiol. Dis., 2011, vol. 41, pp. 62–70. .https://doi.org/10.1016/j.nbd.2010.08.020

    CAS  Article  PubMed  Google Scholar 

  27. Iwasaki, K., Egashira, N., Takagaki, Y., Yoshimitsu, Y., Hatip-Al-Khatib, I., Mishima, K., and Fujiwara, M., Biol. Pharm. Bull., 2007, vol. 30, pp. 698–701. https://doi.org/10.1248/bpb.30.698

    CAS  Article  PubMed  Google Scholar 

  28. Clinical Trials. gov. ID NCT02017340.

  29. Xia, Y., Liu, R., Chen, R., Tian, Q., Zeng, K., Hu, J., Liu, X., Wang, Q., Wang, P., Wang, X.C., and Wang, J.Z., Alzheimers Dis., 2014, vol. 42, pp. 1029–1039. https://doi.org/10.3233/JAD-140597

    CAS  Article  Google Scholar 

  30. Norman, G., Brooks, S.P., Hennebry, G.M., Eacott, M.J., and Little, H.J., J. Psychopharmacol., 2002, vol. 16, pp. 153–161. https://doi.org/10.1177/026988110201600206

    CAS  Article  PubMed  Google Scholar 

  31. Ferreira, G., Yi, J., Ríos, E., and Shirokov, R., J. Gen. Physiol., 1997, vol. 109, pp. 449–461. https://doi.org/10.1085/jgp.109.4.449

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. Fu, H., Li, W., Lao, Y., Luo, J., Lee, N.T.K., Kan, K.K.W., Tsang, H.W., Tsim, K.W.K., Pang, Y., Li, Z., Chang, D.C., Li M., and Han, Y., J. Neurochem., 2006, vol. 98, pp. 1400–1410. https://doi.org/10.1111/j.1471-4159.2006.03960.x

    CAS  Article  PubMed  Google Scholar 

Download references

Funding

The project was supported by the Science and Technology Project of Sichuan Province (no. 2018JY0230) and the Scientific Research Foundation for the Returned Overseas Chinese Scholars from the State Ministry of Education (no. 2015-311).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Li Wang.

Ethics declarations

COMPLIANCE WITH ETHICAL STANDARDS

This article doesnot contain any studies involving human participants performed by any of the authors and doesnot contain any studies involving animals performed by any of the author.

Conflict of Interests

The authors report no conflicts of interest.

Supplementary Information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Xiu, F., Xu, S., Zhang, C. et al. Synthesis and Bio-Evaluation of N-Benzylpiperidine-8-Hydroxyquinoline Derivatives as Potential Cholinesterase Inhibitors, Metal Ion Chelators and Calcium Channel Blockers. Russ J Bioorg Chem 47, 524–534 (2021). https://doi.org/10.1134/S1068162021020266

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S1068162021020266

Keywords:

  • cholinesterase inhibitors
  • calcium channel blocker
  • metal ion chelators
  • multi-target-directed ligands