Derivatives of Betulin and Betulinic Acid Containing a Phosphonate Group—In Silico Studies and Preliminary In Vitro Assessment of Antiviral Activity
Source abstract
Abstract
Viral diseases affecting both humans and animals are a serious public problem. Chemical modifications of the structure of compounds of natural origin, e.g., betulin, seem to be a promising model in the search for new antiviral agents. The subject of our work was to conduct preliminary tests on the antiviral activity of phosphonic derivatives of betulin and betulinic acid and to assess the pharmacokinetic profile of target compounds. Human (HHV-1, HAdV-5) and animal viruses (BEV, VSV) were used in the in vitro tests. Additionally, this paper presents the results of research using in silico methods (ADMET and molecular docking). Two compounds (betulin 29-phosphonate 3 and 3-(3′,3′-dimethylsuccinyl)betulin acid 29-phosphonate 8a) showed antiviral activity against BEV, and compound 3 was also active against HAdV-5. For compound 3, which showed advantageous pharmacokinetic parameters, molecular docking was performed to determine possible interactions with the cellular target HAdV-5 endopeptidase, which plays an important role in various functions of the virus. Selecting the most active derivatives makes it possible to plan tests on an animal model.
Source: crossref · Quality: baseline
Research context
OpenAlex topics: Natural product bioactivities and synthesis · Pharmacological Effects of Natural Compounds · Plant biochemistry and biosynthesis
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
Affiliations
Department of Organic Chemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, 4 Jagiellońska Str., 41-200 Sosnowiec, Poland
Zagórze Pharmacy, 108 Teofila Lenartowicza Str., 41-219 Sosnowiec, Poland
Laboratory of Virology, Department of Immunology of Infectious Diseases, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 Rudolfa Weigla Str., 53-114 Wrocław, Poland
Funding
Medical University of Silesia
References (77)
Show source-provided references
1. Medicinal plants: Treasure for antiviral drug discovery10.1002/ptr.7039 ↗
2. Musarra-Pizzo, M., Pennisi, R., Ben-Amor, I., Mandalari, G., and Sciortino, M.T. (2021). Antiviral Activity Exerted by Natural Products against Human Viruses. Viruses, 13.10.3390/v13050828 ↗
3. Perera, W.P.R.T., Liyanage, J.A., Dissanayake, K.G.C., Gunathilaka, H., Weerakoon, W.M.T.D.N., Wanigasekara, D.N., Fernando, W.S.K., Rajapaksha, R.M.H., Liyanage, R.P., and Perera, B.T. (2021). Antiviral Potential of Selected Medicinal Herbs and Their Isolated Natural Products. Biomed. Res. Int., 2021.10.1155/2021/7872406 ↗
4. A status report with critical analysis of research trends in exploring medicinal plants as antiviral: Let us dig into the history to predict the future10.1002/ptr.7093 ↗
5. Natural Products as Potential Antiviral Drugs: The Specific Case of Marine Biotoxins10.1134/S1068162021060133 ↗
6. Saifulazmi, N.F., Rohani, E.R., Harun, S., Bunawan, H., Hamezah, H.S., Nor Muhammad, N.A., Azizan, K.A., Ahmed, Q.U., Fakurazi, S., and Mediani, A. (2022). A Review with Updated Perspectives on the Antiviral Potentials of Traditional Medicinal Plants and Their Prospects in Antiviral Therapy. Life, 12.10.3390/life12081287 ↗
7. World Health Organization (WHO) (2021). Global Progress Report on HIV, Viral Hepatitis and Sexually Transmitted Infections, World Health Organization. Available online: https://www.who.int/publications/i/item/9789240027077.
8. Origin and evolution of pathogenic coronaviruses10.1038/s41579-018-0118-9 ↗
9. Human coronaviruses: Origin, host and receptor10.1016/j.jcv.2022.105246 ↗
10. Burrell, C.J., Howard, C.R., and Murphy, F.A. (2017). Fenner and White’s Medical Virology, Academic Press. [5th ed.]. Chapter 13.
11. Risk perception associated with an emerging agri-food risk in Europe: Plant viruses in agriculture10.1186/s40066-022-00366-5 ↗
12. Murcia, P., Donachie, W., and Palmarini, M. (2009). Viral pathogens of domestic animals and their impact on biology, medicine and agri-culture. Encycl. Microbiol. (Third Ed.), 805–819.10.1016/B978-012373944-5.00368-0 ↗
13. Human Adenovirus Infections in Pediatric Population—An Update on Clinico–Pathologic Correlation10.1016/j.bj.2021.08.009 ↗
14. Puig-Barberà, J., Mira-Iglesias, A., Burtseva, E., Cowling, J., Serhat, U., Ruiz-Palacios, G.M., Launay, O., Kyncl, J., Koul, P., and Siqueira, M.M. (2019). Influenza epidemiology and influenza vaccine effectiveness during the 2015–2016 season: Results from the Global Influenza Hospital Surveillance Network. BMC Infect. Dis., 19.10.1186/s12879-019-4017-0 ↗
15. Global Burden of Cancer Attributable to Infections in 2018: A Worldwide Incidence Analysis10.1016/S2214-109X(19)30488-7 ↗
16. The Picornaviridae Family: Knowledge gaps, animal models, countermeasures, and prototype pathogens10.1093/infdis/jiac426 ↗
17. Shepherd, J.G., Davis, C., Streicker, D.G., and Thomson, E.C. (2023). Emerging Rhabdoviruses and Human Infection. Biology, 12.10.3390/biology12060878 ↗
18. Long, S.S., Prober, C.G., and Fischer, M. (2018). Principles and Practice of Pediatric Infectious Diseases, Elsevier Inc.
19. Antiviral activity of plants and their isolated bioactive compounds: An update10.1002/ptr.6575 ↗
20. Liu, Y., Yang, L., Wang, H., and Xiong, Y. (2022). Recent Advances in Antiviral Activities of Triterpenoids. Pharmaceuticals, 15.10.3390/ph15101169 ↗
21. Antiviral Activity of Acyl Derivatives of Betulin and Betulinic and Dihydroquinopimaric Acids10.1134/S1068162018050059 ↗
22. Anti-AIDS agents, 11. Betulinic acid and platanic acid as anti-HIV principles from Syzigium claviflorum, and the anti-HIV activity of structurally related triterpenoids10.1021/np50104a008 ↗
23. Antiviral activity of betulin, betulinic and betulonic acids against some enveloped and non-enveloped viruses10.1016/S0367-326X(03)00123-0 ↗
24. The synergistic effects of betulin with acyclovir against herpes simplex viruses10.1016/j.antiviral.2004.05.006 ↗
25. Pentacyclic triterpenes in birch bark extract inhibit early step of herpes simplex virus type 1 replication10.1016/j.phymed.2014.06.007 ↗
26. Inhibition of Epstein-Barr Virus by the Triterpenoid Betulin Diphosphate and Uvaol
27. Synthesis of new betulinic acid/betulin-derived dimers and hybrids with potent antimalarial and antiviral activities10.1016/j.bmc.2018.11.018 ↗
28. Betulin-derived compounds as inhibitors of alphavirus replication10.1021/np9003245 ↗
29. A comparison of the antiviral activity of three triterpenoids isolated from Betula alba bark
30. Bębenek, E., Jastrzębska, M., Kadela-Tomanek, M., Chrobak, E., Orzechowska, B., Zwolińska, K., Latocha, M., Mertas, A., Czuba, Z., and Boryczka, S. (2017). Novel Triazole Hybrids of Betulin: Synthesis and Biological Activity Profile. Molecules, 22.10.3390/molecules22111876 ↗
31. Alhadrami, H.A., Sayed, A.M., Sharif, A.M., Azhar, E.I., and Rateb, M.E. (2021). Olive-Derived Triterpenes Suppress SARS-CoV-2 Main Protease: A Promising Scaffold for Future Therapeutics. Molecules, 26.10.3390/molecules26092654 ↗
32. Betulinic Acid, The First Lupane-Type Triterpenoid Isolated from Both a Phomopsis sp. and Its Host Plant Diospyros carbonaria Benoist10.1002/cbdv.201600171 ↗
33. Pharmacological intervention of HIV-1 maturation10.1016/j.apsb.2015.05.004 ↗
34. Antiviral drugs for cytomegalovirus diseases10.1016/j.antiviral.2006.05.002 ↗
35. Study of chemical stability of antivirally active 5-azacytosine acyclic nucleoside phosphonates using NMR spectroscopy10.1016/j.bmc.2008.05.058 ↗
36. Intralesional cidofovir for the treatment of multiple and recalcitrant cutaneous viral warts10.1111/j.1529-8019.2012.01477.x ↗
37. Chrobak, E., Marciniec, K., Dąbrowska, A., Pęcak, P., Bębenek, E., Kadela-Tomanek, M., Bak, A., Jastrzębska, M., and Boryczka, S. (2019). New Phosphorus Analogs of Bevirimat: Synthesis, Evaluation of Anti-HIV-1 Activity and Molecular Docking Study. Int. J. Mol. Sci., 20.10.3390/ijms20205209 ↗
38. Chrobak, E., Bębenek, E., Kadela-Tomanek, M., Latocha, M., Jelsch, C., Wenger, E., and Boryczka, S. (2016). Betulin Phosphonates; Synthesis, Structure, and Cytotoxic Activity. Molecules, 21.10.3390/molecules21091123 ↗
39. Kuhn, J.H. (2021). Virus taxonomy. Encycl. Virol., 28–37.10.1016/B978-0-12-809633-8.21231-4 ↗
40. An improved colorimetric assay for interleukin 210.1016/0022-1759(86)90183-3 ↗
41. Optimization of sodium dodecyl sulphate as a formazan solvent and comparison of 3-(4,-5-dimethylthiazo-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay with WST-1 assay in MCF-7 cells10.14499/indonesianjpharm25iss4pp245 ↗
42. Novel betulin dicarboxylic acid ester derivatives as potent antiviral agents: Design, synthesis, biological evaluation, structure-activity relationship and in-silico study10.1016/j.ejmech.2021.113738 ↗
43. Antiviral Activity of Isoimperatorin Against Influenza A Virus in vitro and its Inhibition of Neuraminidase10.3389/fphar.2021.657826 ↗
44. Profiles of Drug Substances
45. pkCSM: Predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures10.1021/acs.jmedchem.5b00104 ↗
46. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules10.1038/srep42717 ↗
47. Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., Mennucci, B., and Petersson, G.A. (Gaussian 16, 2016). Gaussian 16, Revision, A. 03. 2016.
48. Dennington, R., Keith, T., and Millam, J. (GaussView, 2009). GaussView, Version 5.
49. Foresman, J.B., and Frisch, A.E. (1996). Exploring Chemistry with Electronic Structure Methods: A Guide to Using Gaussian, Gaussian Inc.
50. Discovery and structure-based optimization of adenain inhibitors10.1021/ml500224t ↗
51. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility10.1002/jcc.21256 ↗
52. Biovia, D.S. (2023, August 20). Discovery Studio Modeling Environment, Dessault Systemes. Available online: https://www.3dsbiovia.com/products/collaborative-science/.
53. LigPlot+: Multiple ligand-protein interaction diagrams for drug discovery10.1021/ci200227u ↗
54. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading10.1002/jcc.21334 ↗
55. Marciniec, K., Chrobak, E., Dąbrowska, A., Bębenek, E., Kadela-Tomanek, M., Pęcak, P., and Boryczka, S. (2020). Phosphate Derivatives of 3-Carboxyacylbetulin: Synthesis, In Vitro Anti-HIV and Molecular Docking Study. Biomolecules, 10.10.3390/biom10081148 ↗
56. HaCaT Keratinocytes Response on Antimicrobial Atelocollagen Substrates: Extent of Cytotoxicity, Cell Viability and Proliferation10.3390/jfb5020043 ↗
57. Naïve Bayesian Models for Vero Cell Cytotoxicity10.1007/s11095-018-2439-9 ↗
58. (2006). Chemical Disinfectants and Antiseptics–Quantitative Suspension Test for the Evaluation of Virucidal Activity of Chemical Disinfectants and Antiseptics Used in the Veterinary Area–Test Method and Requirements (Standard No. PN-EN 14675).
59. A study regarding bovine enterovirus type 1 infection in domestic animals and humans: An evaluation from the zoonotic aspect10.1292/jvms.18-0704 ↗
60. Bishnoi, S., Tiwari, R., Gupta, S., Byrareddy, S.N., and Nayak, D. (2018). Oncotargeting by Vesicular Stomatitis Virus (VSV): Advances in Cancer Therapy. Viruses, 10.10.3390/v10020090 ↗
61. Herpes simplex virus: Global infection prevalence and incidence estimates, 201610.2471/BLT.19.237149 ↗
62. Antiviral activity of triptolide on herpes simplex virus in vitro10.1002/iid3.667 ↗
63. Computational Approaches in Preclinical Studies on Drug Discovery and Development10.3389/fchem.2020.00726 ↗
64. Anti-HIV and antihepatitis C virus drugs inhibit P-glycoprotein efflux activity in Caco-2 cells and precision-cut rat and human intestinal slices10.1128/AAC.00910-19 ↗
65. Clinically Important Drug Interactions Potentially Involving Mechanism-based Inhibition of Cytochrome P450 3A4 and the Role of Therapeutic Drug Monitoring10.1097/FTD.0b013e31815c16f5 ↗
66. Drug-likeness scoring based on unsupervised learning10.1039/D1SC05248A ↗
67. Dehelean, C.A., Marcovici, I., Soica, C., Mioc, M., Coricovac, D., Iurciuc, S., Cretu, O.M., and Pinzaru, I. (2021). Plant-Derived Anticancer Compounds as New Perspectives in Drug Discovery and Alternative Therapy. Molecules, 26.10.3390/molecules26041109 ↗
68. Madej, M., Kurowska, N., and Strzalka-Mrozik, B. (2022). Polymeric Nanoparticles—Tools in a Drug Delivery System in Selected Cancer Therapies. Appl. Sci., 12.10.3390/app12199479 ↗
69. DFT calculations on molecular structures, HOMO–LUMO study, reactivity descriptors and spectral analyses of newly synthesized diorganotin(IV) 2-chloridophenylacetohydroxamate complexes10.1002/jcc.26012 ↗
70. Structural, vibrational and quantum chemical investigations for 6,7-dichloro-2-methyl-5,8-quinolinedione. Cytotoxic and molecular docking studies10.1016/j.molstruc.2018.05.031 ↗
71. Structural and spectral characterisation of 2-amino-2H-[1,2,3]triazolo[4,5-g]quinoline-4,9-dione polymorphs. Cytotoxic activity and molecular docking study with NQO1 enzyme10.1016/j.saa.2020.118038 ↗
72. Rauk, A. (2001). Orbital Interaction Theory of Organic Chemistry, Wiley & Sons John. [2nd ed.].10.1002/0471220418 ↗
73. Kazachenko, A.S., Akman, F., Vasilieva, N.Y., Issaoui, N., Malyar, Y.N., Kondrasenko, A.A., Borovkova, V.S., Miroshnikova, A.V., Kazachenko, A.S., and Al-Dossary, O. (2022). Catalytic sulfation of betulin with sulfamic acid: Experiment and DFT calculation. Int. J. Mol. Sci., 23.10.3390/ijms23031602 ↗
74. Ali, B., Khalid, M., Asim, S., Khan, M.U., Iqbal, Z., Hussain, A., Hussain, R., Ahmed, S., Ali, A., and Hussain, A. (2021). Key electronic, linear and nonlinear optical properties of designed disubstituted quinoline with carbazole compounds. Molecules, 26.10.3390/molecules26092760 ↗
75. Structural, spectral, thermodynamical, NLO, HOMO, LUMO and NBO analysis of fluconazole10.1016/j.saa.2015.06.018 ↗
76. Molecular electrostatic potentials: An effective tool for the elucidation of biochemical phenomena10.1289/ehp.8561191 ↗
77. Adenain, the adenovirus endoprotease (a review)10.1556/AMicr.50.2003.1.9 ↗