Skip to main content

Advertisement

SpringerLink
Log in

Synthesis of berberine derivatives and their antiviral activity toward respiratory syncytial virus

  • Original Research Article
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

Abstract

A series of derivatives of berberine was synthesized to estimate their antiviral activity toward respiratory syncytial virus. Berberine and its hydrogenated analogs were modified at different positions with various substituents. The antiviral activity of berberine and its derivatives against respiratory syncytial virus strain A2 was studied in vitro. Berberine itself and its 12-nitro and 9-O derivatives having heterocyclic motifs in the substituent were shown to have the highest antiviral activity, with half-maximal inhibitory concentration in the lower range (<10 μM). It was found that half-maximal cytotoxic concentration of the compounds varies widely, from 9 to >2000 μM. The selectivity of most compounds under study was below a desired threshold; only berberine, 12-nitroberberine, and tetrahydroberberine can be considered promising for the development of drugs for respiratory syncytial infection.

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
Scheme 1
Scheme 2

Similar content being viewed by others

References

  1. Falsey AR, Walsh EE. Respiratory syncytial virus infection in adults. Clin Microbiol Rev. 2000;13(3):371–84. https://doi.org/10.1128/cmr.13.3.371-384.2000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hall CB, Weinberg GA, Iwane MK, Blumkin AK, Edwards KM, Staat MA, Szilagyi P. The burden of respiratory syncytial virus infection in young children. N Engl J Med. 2009;360:588–98. https://doi.org/10.1056/NEJMoa0804877

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Nair H, Nokes DJ, Gessner BD, Dherani M, Madhi SA, Singleton RJ, Campbell H. Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis. Lancet. 2010;375(9725):1545–55. https://doi.org/10.1016/S0140-6736(10)60206-1

    Article  PubMed  PubMed Central  Google Scholar 

  4. Lambert L, Sagfors AM, Openshaw PJM, Culley FJ. Immunity to RSV in early-life. Front Immunol. 2014;5:466. https://doi.org/10.3389/fimmu.2014.00466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Collins PL, Melero JA. Progress in understanding and controlling respiratory syncytial virus: still crazy after all these years. Virus Res. 2011;162(1-2):80–99. https://doi.org/10.1016/j.virusres.2011.09.020

    Article  CAS  Google Scholar 

  6. Dudas RA, Karron RA. Respiratory syncytial virus vaccines. Clin Microbiol Rev. 1998;11(3):430–9. https://doi.org/10.1128/CMR.11.3.430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kneyber MC, Moll HA, de Groot R. Treatment and prevention of respiratory syncytial virus infection. Eur J Pediatr. 2000;159(6):399–411. https://doi.org/10.1007/s004310051296

    Article  CAS  PubMed  Google Scholar 

  8. Pelaez A, Lyon GM, Force SD, Ramirez AM, Neujahr DC, Foster M, Lawrence EC. Efficacy of oral ribavirin in lung transplant patients with respiratory syncytial virus lower respiratory tract infection. J Heart Lung Transplant. 2009;28(1):67–71. https://doi.org/10.1016/j.healun.2008.10.008

    Article  PubMed  PubMed Central  Google Scholar 

  9. Broadbent L, Groves H, Shields MD, Power UF. Respiratory syncytial virus, an ongoing medical dilemma: an expert commentary on respiratory syncytial virus prophylactic and therapeutic pharmaceuticals currently in clinical trials. Influenza Other Respir Viruses. 2015;9(4):169–78. https://doi.org/10.1111/irv.12313

    Article  PubMed  PubMed Central  Google Scholar 

  10. Lee BH, Chathuranga K, Uddin MB, Weeratunga P, Kim MS, Cho WK, Lee JS. Coptidis Rhizoma extract inhibits replication of respiratory syncytial virus in vitro and in vivo by inducing antiviral state. J Microbiol. 2017;55(6):488–98. https://doi.org/10.1007/s12275-017-7088-x

    Article  CAS  PubMed  Google Scholar 

  11. Thomford NE, Senthebane DA, Rowe A, Munro D, Seele P, Maroyi A, Dzobo K. Natural products for drug discovery in the 21st Century: Innovations for novel drug discovery. Int J Mol Sci. 2018;19(6):1578. https://doi.org/10.3390/ijms19061578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Jassim SA, Naji MA. Novel antiviral agents: a medicinal plant perspective. J Appl Microbiol. 2003;95(3):412–27. https://doi.org/10.1046/j.1365-2672.2003.02026.x

    Article  CAS  PubMed  Google Scholar 

  13. Denaro M, Smeriglio A, Barreca D, De Francesco C, Occhiuto C, Milano G, Trombetta D. Antiviral activity of plants and their isolated bioactive compounds: An update. Phytother Res. 2020;34(4):742–68. https://doi.org/10.1002/ptr.6575

    Article  PubMed  Google Scholar 

  14. Owen L, Laird K, Shivkumar M. Antiviral plant-derived natural products to combat RNA viruses: Targets throughout the viral life cycle. Lett Appl Microbiol. 2022;75(3):476–99. https://doi.org/10.1111/lam.13637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Marchant D, Singhera GK, Utokaparch S, Hackett TL, Boyd JH, Luo Z, Hegele RG. Toll-like receptor 4-mediated activation of p38 mitogen-activated protein kinase is a determinant of respiratory virus entry and tropism. J Virol. 2010;84(21):11359–73. https://doi.org/10.1128/JVI.00804-10

    Article  CAS  PubMed Central  Google Scholar 

  16. Warowicka A, Nawrot R, Goździcka-Józefiak A. Antiviral activity of berberine. Arch Virol. 2020;165(9):1935–45. https://doi.org/10.1007/s00705-020-04706-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Tan L, Wang Y, Ai G, Luo C, Chen H, Li C, Chen J, Su Z. Dihydroberberine, a hydrogenated derivative of berberine firstly identified in Phellodendri Chinese Cortex, exerts anti-inflammatory effect via dual modulation of NF-κB and MAPK signaling pathways. Int Immunopharmacol. 2019;75:105802. https://doi.org/10.1016/j.intimp.2019.105802

    Article  CAS  PubMed  Google Scholar 

  18. Yu X, Yu S, Chen L, Liu H, Zhang J, Ge H, Kou J. Tetrahydroberberrubine attenuates lipopolysaccharide-induced acute lung injury by down-regulating MAPK, AKT, and NF-κB signaling pathways. Biomed Pharmacother. 2016;82:489–97. https://doi.org/10.1016/j.biopha.2016.05.025

    Article  CAS  PubMed  Google Scholar 

  19. Sokolova AS, Yarovaya OI, Kuzminykh LV, Shtro AA, Klabukov AM, Galochkina AV, Salakhutdinov NF. Discovery of N-Containing (-)-Borneol Esters as Respiratory syncytial virus fusion inhibitors. Pharmaceuticals (Basel). 2022;15(11):1390. https://doi.org/10.3390/ph15111390

    Article  CAS  PubMed  Google Scholar 

  20. Khomenko TM, Shtro AA, Galochkina AV, Nikolaeva YV, Petukhova GD, Borisevich SS, Salakhutdinov NF. Monoterpene-containing substituted coumarins as inhibitors of respiratory Syncytial Virus (RSV) Replication. Molecules. 2021;26(24):7493. https://doi.org/10.3390/molecules26247493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Fan T, Hu X, Tang S, Liu X, Wang Y, Deng H, Song D. Discovery and development of 8-substituted cycloberberine derivatives as novel antibacterial agents against MRSA. ACS Med Chem Lett. 2018;9(5):484–9. https://doi.org/10.1021/acsmedchemlett.8b00094

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Jeyakkumar P, Liu HB, Gopala L, Cheng Y, Peng XM, Geng RX, Zhou CH. Novel benzimidazolyl tetrahydroprotoberberines: Design, synthesis, antimicrobial evaluation and multi-targeting exploration. Bioorg Med Chem Lett. 2017;27:1737–43. https://doi.org/10.1016/j.bmcl.2017.02.071

    Article  CAS  PubMed  Google Scholar 

  23. Das B, Srinivas KVNS. Conversion of berberine into berberrubine by selective demethylation under microwave irradiation. Synth Commun. 2002;32(19):3027–9. https://doi.org/10.1081/SCC-120012993

    Article  CAS  Google Scholar 

  24. Iwasa K, Kamigauchi M. 13-hydroxylation of tetrahydroberberine in cell suspension cultures of some Corydalis species. Phytochemistry. 1996;41(6):1511–5. https://doi.org/10.1016/0031-9422(95)00813-6

    Article  CAS  Google Scholar 

  25. Iwasa K, Lee DU, Kang SI, Wiegrebe W. Antimicrobial activity of 8-alkyl- and 8-phenyl-substituted berberines and their 12-bromo derivatives. J Nat Prod. 1998;61(9):1150–3. https://doi.org/10.1021/np980044+

    Article  CAS  PubMed  Google Scholar 

  26. Nechepurenko IV, Shirokova ED, Khvostov MV, Frolova TS, Sinitsyna OI, Maksimov AM, Salakhutdinov NF. Synthesis, hypolipidemic and antifungal activity of tetrahydroberberrubine sulfonates. Russ Chem Bull. 2019;68:1052–60. https://doi.org/10.1007/s11172-019-2519-y

    Article  CAS  Google Scholar 

  27. Gladkova ED, Chepanova AA, Ilina ES, Zakharenko AL, Reynisson J, Luzina OA, Salakhutdinov NF. Discovery of Novel Sultone fused berberine derivatives as promising Tdp1 inhibitors. Molecules. 2021;26(7):1945. https://doi.org/10.3390/molecules26071945

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Shin HB, Choi MS, Yi CM, Lee J, Kim NJ, Inn KS. Inhibition of respiratory syncytial virus replication and virus-induced p38 kinase activity by berberine. Int Immunopharmacol. 2015;27(1):65–8. https://doi.org/10.1016/j.intimp.2015.04.045

    Article  CAS  PubMed  Google Scholar 

  29. Wang B, Deng AJ, Li ZH, Wang N, Qin HL. Syntheses and structure-activity relationships in growth inhibition activity against human cancer cell lines of 12 Substituted Berberine derivatives. Molecules. 2020;25(8):1871. https://doi.org/10.3390/molecules25081871

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Li N, Chen C, Zhu H, Shi Z, Sun J, Chen L. Discovery of novel celastrol-triazole derivatives with Hsp90-Cdc37 disruption to induce tumor cell apoptosis. Bioorg Chem. 2021;111:104867. https://doi.org/10.1016/j.bioorg.2021.104867

    Article  CAS  PubMed  Google Scholar 

  31. Krivitskaya VZ, Petrova ER, Sorokin EV, Tsareva TR, Sverlova MV, Fadeev AV, Sominina AA. Obtaining and characterization of monoclonal antibodies specific to respiratory syncytial virus. Biotechnology. 2016;1:65–75

    Google Scholar 

  32. Reed LJ, Muench H. A simple method of estimating fifty percent endpoints. Am J Epidemiol. 1938;27(3):493–7. https://doi.org/10.1093/oxfordjournals.aje.a118408

    Article  Google Scholar 

Download references

Acknowledgements

The authors would like to acknowledge the Multi-Access Chemical Research Center SB RAS for spectral and analytical measurements. The English language was corrected and certified by shevchuk-editing.com.

Funding

This study was funded by the Russian Science Foundation (Moscow, Russia), grant 21-13-00026.

Author information

Authors and Affiliations

  1. Smorodintsev Research Institute of Influenza, 15/17 Prof. Popov Str., Saint Petersburg, 197376, Russia

    Anna A. Shtro, Anastasia V. Galochkina, Yulia V. Nikolaeva, Angelika V. Garshinina, Darya N. Razgulyaeva, Evgeniy V. Sorokin & Tatyana R. Tsareva

  2. N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of Russian Academy of Sciences, 9 Akademika Lavrentieva Ave., Novosibirsk, 630090, Russia

    Elizaveta D. Gladkova, Olga A. Luzina & Nariman F. Salakhutdinov

Authors
  1. Anna A. Shtro
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elizaveta D. Gladkova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anastasia V. Galochkina
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yulia V. Nikolaeva
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Angelika V. Garshinina
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Darya N. Razgulyaeva
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Evgeniy V. Sorokin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tatyana R. Tsareva
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Olga A. Luzina
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Nariman F. Salakhutdinov
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Olga A. Luzina.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shtro, A.A., Gladkova, E.D., Galochkina, A.V. et al. Synthesis of berberine derivatives and their antiviral activity toward respiratory syncytial virus. Med Chem Res 32, 2325–2333 (2023). https://doi.org/10.1007/s00044-023-03138-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-023-03138-3

Search

Navigation