Skip to main content

Advertisement

SpringerLink
Log in

Synthesis and in vitro activity of oleanolic acid derivatives against Chlamydia trachomatis and Staphylococcus aureus

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

Abstract

A series of nitrogen-containing modificants with amide, arylidene or heterocyclic fragments of oleanolic, oleanonic and 2,3-indolo-oleanolic acids have been synthesized and evaluated for activity against C. trachomatis and key ESKAPE pathogens. Oleanolic acid conjugates with homopyperazine 3, N-hydroxymethyl-homopyperazine 4, and diethylenetriamine 23 demonstrated a high inhibitory activity against C. trachomatis with chemotherapeutic index (CTI) 8 and >8, while 3-amino-3,4-seco-4(23)-en-erythrodiol 22 was found to be a leader compound with significant activity (MIC 3.125 μg/mL). Compounds 3 and 22 showed a moderate activity against MRSA with MICs of 8 and 4 μg/mL. Compounds 2, 3, and 23 exhibited remarkable activities against NCI-60 subpanel (GI50 ranges from 0.18 to 2.21 μM) exceeding the activity of sorafenib with compound 23 as a leader (GI50 0.17 μM for melanoma LOX IMVI).

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

Similar content being viewed by others

References

  1. Pollier J, Goossens A. Oleanolic acid. Phytochem 2012;77:10–15. https://doi.org/10.1016/j.phytochem.2011.12.022

    Article  CAS  Google Scholar 

  2. Sultana N, Ata A. Oleanolic acid and related derivatives as medicinally important compounds. J Enzym Inhib Med Chem. 2008;23:739–56. https://doi.org/10.1080/14756360701633187

    Article  CAS  Google Scholar 

  3. Vyas N, Argal A. Isolation and characterization of oleanolic acid from roots of Lantana camara. Asian J Pharm Clin Res. 2014;7:189–91.

    Google Scholar 

  4. Xia EQ, Wang BW, Xu XR, Zhu L, Song Y, Li HB. Microwave-assisted extraction of oleanolic acid and ursolic acid from Ligustrum lucidum. Ait Int J Mol Sci. 2011;12:5319–29. https://doi.org/10.3390/ijms12085319

    Article  CAS  PubMed  Google Scholar 

  5. Verma SC, Jain CL, Nigam S, Padhi MM. Rapid extraction, isolation, and quantification of oleanolic acid from Lantana camara L. roots using microwave and HPLC-PDA techniques. Acta Chromatogr. 2013;25:181–99. https://doi.org/10.1556/AChrom.25.2013.1.12

    Article  CAS  Google Scholar 

  6. Kim S, Lee H, Lee S, Yoon Y, Choi K-H. Antimicrobial action of oleanolic acid on listeria monocytogenes, enterococcus faecium, and enterococcus faecalis. PLoS ONE. 2015;10:e0118800. https://doi.org/10.1371/journal.pone.0118800

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wang J, Ren H, Xu QL, Zhou ZY, Wu P, Wei XY, et al. Antibacterial oleanane-type triterpenoids from pericarps of Akebia trifoliate. Food Chem. 2015;168:623–29. https://doi.org/10.1016/j.foodchem.2014.07.105

    Article  CAS  PubMed  Google Scholar 

  8. Ye M, Liao Y, Wu L, Qi W, Choudhry N, Liu Y, et al. An oleanolic acid derivative inhibits hemagglutinin-mediated entry of influenza A virus. Viruses. 2020;12:225. https://doi.org/10.3390/v12020225

    Article  CAS  PubMed Central  Google Scholar 

  9. Wang X, Ye X, Liu R, Chen HL, Bai H, Liang X. Antioxidant activities of oleanolic acid in vitro: possible role of Nrf2 and MAP kinases. Chem-Biol Interact. 2010;184:328–37. https://doi.org/10.1016/j.cbi.2010.01.034

    Article  CAS  PubMed  Google Scholar 

  10. Castellano JM, Guinda A, Macías L, Santos-Lozano JM, Lapetra J, Rada M. Free radical scavenging and glucosidase inhibition, two potential mechanisms involved in the anti-diabetic activity of oleanolic acid. Grasasy Aceites. 2016;67:e142. https://doi.org/10.3989/gya.1237153

    Article  CAS  Google Scholar 

  11. Shanmugam MK, Dai X, Kumar AP, Tan BK, Sethi G, Bishayee A. Oleanolic acid and its synthetic derivatives for the prevention and therapy of cancer: Preclinical and clinical evidence. Cancer Lett. 2014;346:206–16. https://doi.org/10.1016/j.canlet.2014.01.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Amara S, Zheng M, Tiriveedhi V. Oleanolic acid inhibits high salt-induced exaggeration of warburg-like metabolism in breast cancer cells. Cell Biochem Biophys 2016;74:427–34. https://doi.org/10.1007/s12013-016-0736-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Nyakudya T, Mukwevho E, Nkomozepi P, Swanepoel E, Erlwanger KH. Early postnatal administration of oleanolic acid attenuates the development of non-alcoholic fatty liver disease in fructose fed adult female rats. FASEB J. 2017;31:2. https://doi.org/10.1017/S2040174420000124

    Article  CAS  Google Scholar 

  14. Jesus JJ, Lago JHG, Laurenti MD, Yamamoto ES, Passero LFD. Antimicrobial activity of oleanolic acids. evid based complement alternat med. 2015. https://doi.org/10.1155/2015/620472.

  15. Liu Q, Niu H, Zhang W, Mu H, Sun C, Duan J. Synergy among thymol, eugenol, berberine, cinnamaldehyde and streptomycin against planktonic and biofilm-associated food-borne pathogens. Lett Appl Microbiol. 2015;60:21–30. https://doi.org/10.1111/lam.12401

    Article  CAS  Google Scholar 

  16. Feng A, Yang S, Sun Y, Zhang L, Bo F, Li L. Development and evaluation of oleanolic acid dosage forms and its derivatives. BioMed Res. 2020. https://doi.org/10.1155/2020/1308749. [Online first article]

    Article  Google Scholar 

  17. Chouaïb K, Hichri F, Nguir A, Daami-Remadi M, Elie N, Touboul D, et al. Semi-synthesis of new antimicrobial esters from the natural oleanolic and maslinic acids. Food Chem. 2015;183:8–17. https://doi.org/10.1016/j.foodchem.2015.03.018

    Article  CAS  PubMed  Google Scholar 

  18. Kazakova OB, Brunel JM, Khusnutdinova EF, Negrel S, Giniyatullina GV, Lopatina TV et al. A-ring modified triterpenoids and their spermidine-aldimines with strong antibacterial activity. Molbank. 2019. https://doi.org/10.3390/M1078.

  19. Medvedeva NI, Kazakova OB, Lopatina TV, Smirnova IE, Giniyatullina GV, Baikova IP, et al. Synthesis and antimycobacterial activity of triterpenic A-ring azepanes. Eur J Med Chem. 2018;143:464–72. https://doi.org/10.1016/j.ejmech.2017.11.035

    Article  CAS  PubMed  Google Scholar 

  20. Porritt RA, Crother TR. Chlamydia pneumoniae. Infection and inflammatory diseases. Immunopathol Dis Ther. 2016;7:237–54. https://doi.org/10.1615/ForumImmunDisTher.2017020161

    Article  Google Scholar 

  21. Alakurtti S, Mäkelä T, Koskimies S, Yli-Kauhaluoma J. Pharmacological properties of the ubiquitous natural product betulin. Eur J Pharm Sci. 2006;29:1–13. https://doi.org/10.1016/j.ejps.2006.04.006

    Article  CAS  PubMed  Google Scholar 

  22. Salin O, Alakurtti S, Pohjala L, Siiskonen A, Maass V, Maass M, et al. Inhibitory effect of the natural product betulin and its derivatives against the intracellular bacterium Chlamydia pneumoniae. Biochem Pharm. 2010;80:1141–51. https://doi.org/10.1016/j.bcp.2010.06.051

    Article  CAS  PubMed  Google Scholar 

  23. Tazoo D, Krohn K, Hussain H, Kouam SF, Dongo E. Laportoside A and laportomide A: a new cerebroside and a new ceramide from leaves of Laportea ovalifolia. Z Naturforsch. 2007;62B:12081212.

    Google Scholar 

  24. Antoine KZ, Hussain H, Dongo E, Kouam SF, Schulz B, Krohn K, et al. A new ceramide from Helichrysum cameroonensei. J Asian Nat Prod Res. 2010;12:629–33. https://doi.org/10.1080/10286020.2010.485933

    Article  CAS  PubMed  Google Scholar 

  25. Eyong KO, Krohn K, Hussain H, Folefoc GN, Nkengfack AE, Schulz B, et al. Newbouldiaquinone and Newbouldiamide: a new naphthoquinone-anthraquinone coupled pigment and a new ceramide from Newbouldia laevis. Chem Pharm Bull. 2005;53:616–9. https://doi.org/10.1248/cpb.53.616

    Article  CAS  Google Scholar 

  26. Kazakova OB, Rubanik LV, Smirnova IE, Savinova OV, Petrova AV, Poleschuk NN, et al. Synthesis and in vitro activity of oleanane type derivatives against Chlamydia trachomatis. Org Commun. 2019;12:169–75. https://doi.org/10.25135/acg.oc.66.19.07.1352

    Article  CAS  Google Scholar 

  27. Wu P, Tu B, Liang J, Guo S, Cao N, Chen S, et al. Synthesis and biological evaluation of pentacyclic triterpenoid derivatives as potential novel antibacterial agents. Bioorg Chem. 2021;109:104692. https://doi.org/10.1016/j.bioorg.2021.104692

    Article  CAS  PubMed  Google Scholar 

  28. Bildziukevich U, Vida N, Rárová L, Kolář M, Šaman D, Havlíček L, et al. Polyamine derivatives of betulinic acid and β-sitosterol: a comparative investigation. Steroids. 2015;100:27–35. https://doi.org/10.1016/j.steroids.2015.04.005

    Article  CAS  PubMed  Google Scholar 

  29. Bildziukevich U, Malik M, Özdemir Z, Rárová L, Janovska L, Slouf M et al. Spermine amides of selected triterpenoid acids: dynamic supramolecular systems formation influences cytotoxicity of the drugs. J Mat Chem B. 2019. https://doi.org/10.1039/c9tb01957j.

  30. Blanchet M, Borselli D, Brunel JM. Polyamine derivatives: a revival of an old neglected scaffold to fight resistant Gram-negative bacteria? Future Med Chem. 2016;8:963–73. https://doi.org/10.4155/fmc-2016-0011

    Article  CAS  PubMed  Google Scholar 

  31. Spivak AY, Khalitova RR, Nedopekina DA, Gubaidullin RR. Antimicrobial properties of amine- and guanidine-functionalized derivativesof betulinic, ursolic and oleanolic acids: Synthesis and structure/activity evaluation. Steroids 2020. 2020;154:108530. https://doi.org/10.1016/j.steroids.2019.108530

    Article  CAS  Google Scholar 

  32. Kazakova OB, Giniyatullina GV, Mustafin AG, Babkov DA, Sokolova EV, Spasov AA. Evaluation of cytotoxicity and α-glucosidase inhibitory activity of amide and polyamino-derivatives of lupane triterpenoids. Molecules. 2020;25:4833. https://doi.org/10.3390/molecules25204833

    Article  CAS  PubMed Central  Google Scholar 

  33. la Hoz ADE, Cortés JA. Bacterial and atypical infections in critically ill cancer patients. Oncologic Crit Care. 2019;379–1400. https://doi.org/10.1007/978-3-319-74588-6_123.

  34. Boyd MR, Paul KD. Some practical considerations and applications of the National Cancer Institute in vitro anticancer drug discovery screen. Drug Res Rep. 1995;34:91–109.

    Article  CAS  Google Scholar 

  35. Grever MR, Schepartz SA, Chabner BA. The National Cancer Institute: cancer drug discovery and development program. Semin Oncol. 1992;19:622–38.

  36. Monks A, Scudiero D, Skehan P, Shoemaker R, Paull KD, Vistica D. Feasibility of a highflux anticancer drug screen using a diverse panel of cultured human tumor cell lines. Nat Cancer Inst. 1991;183:757–66.

    Article  Google Scholar 

  37. Monks A, Scudiero DA, Johnson GS, Paull KD, Sausville EA. The NCI anti-cancer drug screen: a smart screen to identify effectors of novel targets. Anti-Cancer Drug Des. 1997;12:533–41.

    CAS  Google Scholar 

  38. Weinstein JN, Myers TG, O’Connor PM, Friend SH Jr, Fornace AJ, Kohn KW. An information-intensive approach to the molecular pharmacology of cancer. Science. 1997;275:343–9. https://doi.org/10.1126/science.275.5298.343

    Article  CAS  PubMed  Google Scholar 

  39. Sahu NP, Mahato SB, Banerji N, Chakravarti RN. Cadambagenic acid. New triterpenic acid from Anthocephalus cadamba. Ind J Chem. 1974;12:284–6.

    CAS  Google Scholar 

  40. Jurstrand M, Falk L, Fredlund H, Lindberg M, Olcen P, Andersson S, et al. Characterization of Chlamydia trachomatis omp1 genotypes among sexually transmitted disease patients in Sweden. J Сlin Microbiol. 2001;39:3915–9. https://doi.org/10.1128/JCM.39.11.3915-3919.2001

    Article  CAS  Google Scholar 

  41. Bednarczyk-Cwynar B, Ruszkowski P, Bobkiewicz-Kozlowska T, Zaprutko L. Oleanolic acid A-lactams inhibit the growth of HeLa, KB, MCF-7 and Hep-G2 cancer cell lines at micromolar concentrations. Anti-Cancer Agents Med Chem. 2016;16:579–92. https://doi.org/10.2174/1871520615666150907095756

    Article  CAS  Google Scholar 

  42. Nie W, Luo JG, Wang XB, Yin H, Sun HB, Yao HQ, et al. Synthesis of new α-glucosidase inhibitors based on oleanolic acid incorporating cinnamic amides. Chem Pharm Bull. 2011;59:1051–6. https://doi.org/10.1248/cpb.59.1051

    Article  CAS  Google Scholar 

  43. Petrova AV, Lopatina TV, Mustafin AG, Kazakova OB. Modification of azepanobetulin at the isopropenyl group. Russ J Org Chem. 2020;56:1582–7. https://doi.org/10.1134/S1070428020090134

    Article  CAS  Google Scholar 

  44. Zaprutko L. Triterpenoids. Part 9. Structure elucidation of a new sodium dichromate oxidation product of methyl oleanolate and some of its derivatives. Pol J Chem. 1995;69:1003–12.

    CAS  Google Scholar 

  45. Kazakova OB, Medvedeva NI, Samoilova IA, Baikova IP, Tolstikov GA, Kataev VE, et al. Conjugates of several lupane, oleanane, and ursane triterpenoids with the antituberculosis drug isoniazid and pyridinecarboxaldehydes. Chem Nat Comp. 2011;47:752–8.

  46. Khusnutdinova EF, Petrova AV, Apryshko GN, Kukovinets OS, Kazakova OB. Synthesis and cytotoxicity of indole derivatives of betulin, erythrodiol, and uvaol. Russ J Bioorg Chem. 2018a;44:322–9. https://doi.org/10.1134/S1068162018030081

    Article  CAS  Google Scholar 

  47. Khusnutdinova EF, Petrova AV, Kukovinets OS, Kazakova OB. Synthesis and cytotoxicity of 28-N-propargylaminoalkylated 2,3-indolotriterpenic acids. Nat Prod Comm. 2018b;13:665–8. https://doi.org/10.1177/1934578X1801300603

    Article  Google Scholar 

  48. Kazakova O, Smirnova I, Lopatina T, Giniyatullina G, Petrova A, Khusnutdinova E, et al. Synthesis and cholinesterase inhibiting potential of A-ring azepano- and 3-amino-3,4-seco-triterpenoids. Bioorg Chem. 2020;101:104001. https://doi.org/10.1016/j.bioorg.2020.104001

    Article  CAS  PubMed  Google Scholar 

  49. Shen Y, Shi D, Tang J, Sui M. Oleanolic acid derivatives, preparation method and application; CN. 2012-10045425.

Download references

Acknowledgements

The reported study was funded by RFBR and BRFBR (project no. 20-53-00014) and the Belarusian Republican Foundation for Fundamental Research (project no. M20P-275). We thank National Cancer Institute for the screening of cytotoxicity for compounds 2, 3, and 23. The antimicrobial screening was performed by CO-ADD (The Community for Antimicrobial Drug Discovery), funded by the Wellcome Trust (UK) and The University of Queensland (Australia).

Author information

Authors and Affiliations

  1. Ufa Institute of Chemistry of the Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russian Federation

    Oxana Kazakova, Irina Smirnova, Anastasia Petrova, Irina Baikova, Elena Tret’yakova & Elmira Khusnutdinova

  2. Republican Research and Practical Center for Epidemiology and Microbiology, Minsk, Belarus

    Liudmila Rubanik, Nikolay Poleschuk & Yuliya Kapustsina

Authors
  1. Oxana Kazakova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Liudmila Rubanik
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Irina Smirnova
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nikolay Poleschuk
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anastasia Petrova
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yuliya Kapustsina
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Irina Baikova
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Elena Tret’yakova
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Elmira Khusnutdinova
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Oxana Kazakova.

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

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kazakova, O., Rubanik, L., Smirnova, I. et al. Synthesis and in vitro activity of oleanolic acid derivatives against Chlamydia trachomatis and Staphylococcus aureus. Med Chem Res 30, 1408–1418 (2021). https://doi.org/10.1007/s00044-021-02741-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-021-02741-6

Keywords

Search

Navigation