Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter December 24, 2020

Cardenolides and pentacyclic triterpenes isolated from Acokanthera oblongifolia leaves: their biological activities with molecular docking study

  • Howaida I. Abd-Alla ORCID logo EMAIL logo , Maha M. Soltan , Amal Z. Hassan , Hanan A. A. Taie , Heba M. Abo-Salem , Eman A. Karam , Mounir M. El-Safty and Atef G. Hanna

Abstract

Pentacyclic triterpenes and cardenolides were isolated from Acokanthera oblongifolia leaves. Their chemical structures were determined based on comprehensive 1D and 2D NMR spectroscopy. Their MIC was determined against 12 microorganisms. Their exerted cytotoxicity on the immortalized normal cells, hTERT-RPE1 was assessed by the sulforhodamine-B assay. The viral inhibitory effects of compounds against Newcastle disease virus (NDV) and H5N1 influenza virus IV were evaluated. Four in vitro antioxidant assays were performed in comparison with BHT and trolox and a weak activity was exhibited. Acovenoside A was with potent against H5N1-IV and NDV with IC50 ≤ 3.2 and ≤ 2.1 μg/ml and SI values of 93.75 and 95.23%, respectively, in comparison to ribavirin. Its CC50 record on Vero cells was > 400 and 200 μg/ml, respectively. Acobioside A was the most active compound against a broad range of microbes while Pseudomonas aeruginosa was the most sensitive. Its MIC (0.07 μg/ml) was 1/100-fold of the recorded CC50 (7.1 μg/ml/72 h) against hTERT-RPE1. The molecular docking of compounds on human DNA topoisomerase I (Top1-DNA) and IV glycoprotein hemagglutinin were studied using MOE program. This study has introduced the cardenolides rather than triterpenoids with the best docking score and binding interaction with the active site of the studied proteins.


Corresponding author: Howaida I. Abd-Alla, Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Division, National Research Centre, Dokki-Giza, 12622, Egypt, E-mail:

Funding source: National Research Centre

Award Identifier / Grant number: 11010324

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: The authors wish to thank the partial financial support of National Research Centre, Egypt of grant number 11010324.

  3. Conflict of interest statement: The authors declare that they have no competing interests.

References

1. Fair, RJ, McCoy, LS, Hensler, ME, Aguilar, B, Nizet, V, Tor, Y. Singly modified amikacin and tobramycin derivatives show increased rRNA A-site binding and higher potency against resistant bacteria. ChemMedChem 2014;9:2164–71.10.1002/cmdc.201402175Search in Google Scholar PubMed PubMed Central

2. Wang, X, Jia, W, Zhao, A, Wang, X. Anti-influenza agents from plants and traditional Chinese medicine. Phytother Res 2006;20:335–41.10.1002/ptr.1892Search in Google Scholar PubMed

3. Chatziprodromidou, IP, Bellou, M, Vantarakis, G, Vantarakis, A. Viral outbreaks linked to fresh produce consumption: a systematic review. J Appl Microbiol 2018;124:932–42.10.1111/jam.13747Search in Google Scholar PubMed

4. Abd-Alla, HI, Abu-Gabal, NS, Hassan, AZ, El-Safty, MM, Shalaby, NM. Antiviral activity of Aloe hijazensis against some haemagglutinating viruses’ infection and its phytoconstituents. Arch Pharm Res 2012;35:1347–54.10.1007/s12272-012-0804-5Search in Google Scholar PubMed PubMed Central

5. Rota, P, La Rocca, P, Piccoli, M, Montefiori, M, Cirillo, F, Olsen, L, et al.. Potent inhibitors against Newcastle disease virus hemagglutinin-neuraminidase. ChemMedChem 2018;13:236–40.10.1002/cmdc.201700755Search in Google Scholar PubMed

6. Mukhtar, M, Arshad, M, Ahmad, M, Pomerantz, RJ, Wigdahl, B, Parveen, Z. Antiviral potentials of medicinal plants. Virus Res 2008;131:111–20.10.1016/j.virusres.2007.09.008Search in Google Scholar PubMed PubMed Central

7. Soltan, MM, Zaki, AK. Antiviral screening of forty-two Egyptian medicinal plants. J Ethnopharmacol 2009;126:102–7.10.1016/j.jep.2009.08.001Search in Google Scholar PubMed

8. Abd-Alla, HI, Heba-tollah, MS, El-Kashak, WA, El-Safty, MM. Evaluation of immune boosting properties and combating of multiple respiratory viral infections by fifteen Euphorbiaceae plant extracts. Pharmacog J 2019;11:1490–503.10.5530/pj.2019.11.230Search in Google Scholar

9. Abd-Alla, HI, Heba-tollah, MS, Mohamed, TA, Gabr, MM, El-Safty, MM, Hegazy, ME. Efficacy of extracts and iridoid glucosides from Pentas lanceolata on humoral and cell-mediated immune response of viral vaccine. Med Chem Res 2017;26:2196–204.10.1007/s00044-017-1935-5Search in Google Scholar

10. Wynn, SG, Fougère, BJ. Veterinary herbal medicine. Can Vet J 2008;49:802.Search in Google Scholar

11. Hartley, C, Hartley, M, Pardoe, I, Knight, A. Ionic contra-viral therapy (ICVT); a new approach to the treatment of DNA virus infections. Arch Virol 2006;151:2495–501.10.1007/s00705-006-0824-xSearch in Google Scholar PubMed

12. Mijatovic, T, Van Quaquebeke, E, Delest, B, Debeir, O, Darro, F, Kiss, R. Cardiotonic steroids on the road to anti-cancer therapy. Biochim Biophys Acta 2007;1776:32–57.10.1016/j.bbcan.2007.06.002Search in Google Scholar

13. Yang, CW, Chang, HY, Hsu, HY, Lee, YZ, Chang, HS, Chen, IS, et al.. Identification of anti-viral activity of the cardenolides, Na+/K+-ATPase inhibitors, against porcine transmissible gastroenteritis virus. Toxicol Appl Pharmacol 2017;332:129–37.10.1016/j.taap.2017.04.017Search in Google Scholar

14. Kapoor, A, Cai, H, Forman, M, He, R, Shamay, M, Arav-Boger, R. Human cytomegalovirus inhibition by cardiac glycosides: evidence for involvement of the HERG gene. Antimicrob Agents Chemother 2012;56:4891–9.10.1128/AAC.00898-12Search in Google Scholar

15. Dodson, AW, Taylor, TJ, Knipe, DM, Coen, DM. Inhibitors of the sodium potassium ATPase that impair herpes simplex virus replication identified via a chemical screening approach. Virology 2007;366:340–8.10.1016/j.virol.2007.05.001Search in Google Scholar

16. Bhat, RB, Jacobs, TV. Traditional herbal medicine in Transkei. J Ethnopharmacol 1995;48:7–12.10.1016/0378-8741(95)01276-JSearch in Google Scholar

17. Ahmed, E, Elkhateeb, W, Taie, H, Rateb, M, Fayad, W. Biological capacity and chemical composition of secondary metabolites from representatives Japanese lichens. J Appl Pharmaceut Sci 2017;7:98–103.10.7324/JAPS.2017.70113Search in Google Scholar

18. Solich, P, Sedliakova, V, Karlíček, R Spectrophotometric determination of cardiac glycosides by flow-injection analysis. Anal Chim Acta 1992;269:199–203.10.1016/0003-2670(92)85403-SSearch in Google Scholar

19. Sun, J, Chen, Y, Li, M, Ge, Z. Role of antioxidant enzymes on ionizing radiation resistance. Free Radic Biol Med 1998;24:586–93.10.1016/S0891-5849(97)00291-8Search in Google Scholar

20. Makkar, HP, Becker, K. Nutritional value and anti-nutritional components of whole and ethanol extracted Moringa oliefera leaves. Anim Feed Sci Technol 1996;63:211–28.10.1016/S0377-8401(96)01023-1Search in Google Scholar

21. Zhishen, J, Mengcheng, T, Jianming, W. The determination of flavonoid contents in mulberry and their scavenging effects on superoxide radicals. Food Chem 1999;64:555–9.10.1016/S0308-8146(98)00102-2Search in Google Scholar

22. Abd-Alla, HI, Albalawy, MA, Aly, HF, Shalaby, NM, Shaker, KH. Flavone composition and antihypercholesterolemic and antihyperglycemic activities of Chrysanthemum coronarium L. Z Naturforsch C Biosci 2014;69:199–208.10.5560/znc.2013-0115Search in Google Scholar PubMed

23. Gora, IM, Kwasnik, M, Zmudzinski, JF, Rozek, W. Chorioallantoic membranes of embryonated chicken eggs as an alternative system for isolation of equine influenza virus. Virol J 2017;14:120.10.1186/s12985-017-0788-3Search in Google Scholar PubMed PubMed Central

24. Penna, CA, Marino, S, Gutkind, GO, Clavin, M, Ferraro, G, Martino, V. Antimicrobial activity of Eupatorium species growing in Argentina. J Herbs, Spices, Med Plants 1998;5:21–8.10.1300/J044v05n02_04Search in Google Scholar

25. Souza, VC, Lorenzi, H. Botânica sistemática: guia ilustrado para identificação das famílias de Angiospermas da flora brasileira, baseado em APGII. Nova Odessa: Instituto Plantarum; 2005:640 p.Search in Google Scholar

26. Galal, AMF, Soltan, MM, Ahmed, ER, Hanna, AG. Synthesis and biological evaluation of novel 5-chloro-N-(4-sulphamoylbenzyl) salicylamide derivatives as tubulin polymerization inhibitors. Med Chem Comm 2018;9:1511–28.10.1039/C8MD00214BSearch in Google Scholar PubMed PubMed Central

27. Skehan, P, Storeng, R, Scudiero, D, Monks, A, McMahon, J, Vistica, D, et al.. New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst 1990;82:1107–12.10.1093/jnci/82.13.1107Search in Google Scholar PubMed

28. Vichai, V, Kirtikara, K. Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc 2006;1:1112–16.10.1038/nprot.2006.179Search in Google Scholar PubMed

29. Staker, BL, Feese, MD, Cushman, M, Pommier, Y, Zembower, D, Stewart, L, et al.. Structures of three classes of anticancer agents bound to the human topoisomerase I-DNA covalent complex. J Med Chem 2005;48:2336–45.10.1021/jm049146pSearch in Google Scholar PubMed

30. Van Dongen, M, Kadam, R, Juraszek, J, Lawson, E, Brandenburg, B, Schmitz, F, et al.. A small-molecule fusion inhibitor of influenza virus is orally active in mice. Science 2019;363:1056.10.1126/science.aar6221Search in Google Scholar PubMed PubMed Central

31. Kaminski, G, Jorgensen, WL. Performance of the AMBER94, MMFF94 and OPLS-AA force fields for modeling organic liquids. J Phys Chem 1996;100:18010–13.10.1021/jp9624257Search in Google Scholar

32. Seebacher, W, Simic, N, Weis, R, Saf, R, Kunert, O. Complete assignments of 1H and 13C NMR resonances of oleanolic acid, 18α‐oleanolic acid, ursolic acid and their 11‐oxo derivatives. Magn Reson Chem 2003;41:636–8.10.1002/mrc.1214Search in Google Scholar

33. Magalhães, CG, Duarte, LP, Mussel, WD, Ruiz, AL, Shiozawa, L, Carvalho, JE, et al.. Lupeol and its esters: NMR, powder XRD data and in vitro evaluation of cancer cell growth. Braz J Pharm Sci 2017;53:e00251.10.1590/s2175-97902017000300251Search in Google Scholar

34. Pieri, F, Arnould-Guerin, ML, Sefraoui, EH. Cardiotonic glycosides from Acokanthera spectabilis. Fitoterapia-Milano 1992;63:333–6.Search in Google Scholar

35. Hanna, AG, Elgamal, MHA, Hassan, AZ, Duddeck, H, Simon, A, Kovács, J, et al.. Complete 1H and 13C signal assignments of 5β-cardenolides isolated from Acokanthera spectabilis Hook F. Magn Reson Chem 1998;36:936–42.10.1002/(SICI)1097-458X(199812)36:12<936::AID-OMR386>3.0.CO;2-0Search in Google Scholar

36. Ezzat, SM, El Gaafary, M, El Sayed, AM, Sabry, OM, Ali, ZY, Hafner, S, et al.. The cardenolide glycoside acovenoside a affords protective activity in doxorubicin-induced cardiotoxicity in mice. J Pharmacol Exp Therapeut 2016;358:262–70.10.1124/jpet.116.232652Search in Google Scholar

37. Kapadia, GJ. Acospectoside a II: the structure of the cardenolide glycoside. J Pharm Sci 1969;58:1555–7.10.1002/jps.2600581235Search in Google Scholar

38. Bertol, JW, Rigotto, C, de Pádua, RM, Kreis, W, Barardi, CR, Braga, FC, et al.. Antiherpes activity of glucoevatromonoside, a cardenolide isolated from a Brazilian cultivar of Digitalis lanata. Antivir Res 2011;92:73–80.10.1016/j.antiviral.2011.06.015Search in Google Scholar

39. Simões, CM, Amoros, M, Girre, L. Mechanism of antiviral activity of triterpenoid saponins. Phytother Res 1999;13:323–8.10.1002/(SICI)1099-1573(199906)13:4<323::AID-PTR448>3.0.CO;2-CSearch in Google Scholar

40. Treml, J, Gazdová, M, Šmejkal, K, Šudomová, M, Kubatka, P, Hassan, ST. Natural products-derived chemicals: breaking barriers to novel anti-HSV drug development. Viruses 2020;12:154.10.3390/v12020154Search in Google Scholar

41. El-Sayed, AM, Ezzat, SM, Sabry, OM. A new antibacterial lupane ester from the seeds of Acokanthera oppositifolia Lam. Nat Prod Res 2016;30:2813–18.10.1080/14786419.2016.1166494Search in Google Scholar

42. Pecio, Ł, Hassan, EM, Omer, EA, Gajek, G, Kontek, R, Sobieraj, A, et al.. Cytotoxic cardenolides from the leaves of Acokanthera oblongifolia. Planta Med 2019;85:965–72.10.1055/a-0958-2566Search in Google Scholar

43. Mcdonnell, G, Russell, AD. Antiseptics and disinfectants: activity, action, and resistance. Clin Microbiol Rev 1999;12:147–79.10.1128/CMR.12.1.147Search in Google Scholar

44. Shaaban, M, Abd-Alla, HI, Hassan, AZ, Aly, HF, Ghani, MA. Chemical characterization, antioxidant and inhibitory effects of some marine sponges against carbohydrate metabolizing enzymes. Org Med Chem Lett 2012;2:30.10.1186/2191-2858-2-30Search in Google Scholar PubMed PubMed Central

45. Awad, HM, Abd-Alla, HI, Mahmoud, KH, El-Toumy, SA. In vitro anti-nitrosative, antioxidant, and cytotoxicity activities of plant flavonoids: a comparative study. Med Chem Res 2014;23:3298–307.10.1007/s00044-014-0915-2Search in Google Scholar

46. Gülçin, I, Alici, HA, Cesur, M. Determination of in vitro antioxidant and radical scavenging activities of propofol. Chem Pharm Bull 2005;53:281–5.10.1248/cpb.53.281Search in Google Scholar PubMed

47. Moukette, BM, Pieme, CA, Njimou, JR, Biapa, CP, Marco, B, Ngogang, JY. In vitro antioxidant properties, free radicals scavenging activities of extracts and polyphenol composition of a non-timber forest product used as spice: Monodora myristica. Biol Res 2015;48:15.10.1186/s40659-015-0003-1Search in Google Scholar PubMed PubMed Central

48. Gerl, R, Vaux, DL. Apoptosis in the development and treatment of cancer. Carcinogenesis 2005;26:263–70.10.1093/carcin/bgh283Search in Google Scholar PubMed

49. Lauria, A, Ippolito, M, Almerico, AM. Molecular docking approach on the Topoisomerase I inhibitors series included in the NCI anti-cancer agents mechanism database. J Mol Model 2007;13:393–400.10.1007/s00894-006-0159-2Search in Google Scholar PubMed

50. Stewart, L, Ireton, GC, Champoux, JJ. Reconstitution of human topoisomerase I by fragment complementation. J Mol Biol 1997;269:355.10.1006/jmbi.1997.1056Search in Google Scholar PubMed

51. Stewart, L, Ireton, GC, Champoux, JJ. A functional linker in human topoisomerase I is required for maximum sensitivity to camptothecin in a DNA relaxation assay. J Biol Chem 1999;274:32950–60.10.1074/jbc.274.46.32950Search in Google Scholar PubMed

52. Basu, A, Antanasijevic, A, Wang, M, Li, B, Mills, DM, Ames, JA, et al.. New small molecule entry inhibitors targeting hemagglutinin mediated influenza a virus fusion. J Virol 2014;88:1447–60.10.1128/JVI.01225-13Search in Google Scholar PubMed PubMed Central

53. 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;12:225.10.3390/v12020225Search in Google Scholar PubMed PubMed Central

54. Ranaweera, A, Ratnayake, PU, Weliky, DP. The stabilities of the soluble ectodomain and fusion peptide hairpins of the influenza virus haemagglutinin subunit II protein are positively correlated with membrane fusion. Biochemistry 2018;57:5480–93.10.1021/acs.biochem.8b00764Search in Google Scholar PubMed PubMed Central

55. Vanderlinden, E, Naesens, L. Emerging antiviral strategies to interfere with influenza virus entry. Med Res Rev 2014;34:301–39.10.1002/med.21289Search in Google Scholar PubMed PubMed Central

56. Yu, M, Si, L, Wang, Y, Wu, Y, Yu, F, Jiao, P, et al.. Discovery of pentacyclic triterpenoids as potential entry inhibitors of influenza viruses. J Med Chem 2014;57:10058–71.10.1021/jm5014067Search in Google Scholar PubMed

Received: 2020-08-07
Accepted: 2020-12-01
Published Online: 2020-12-24
Published in Print: 2021-07-27

© 2020 Walter de Gruyter GmbH, Berlin/Boston

Downloaded on 29.3.2024 from https://www.degruyter.com/document/doi/10.1515/znc-2020-0198/html
Scroll to top button