Medicinal Chemistry Research

, Volume 28, Issue 10, pp 1648–1660 | Cite as

Synthesis and evaluation of antiviral activities of triterpenic conjugates with 2-aminobutan-1-ol as potent microbicidal agents

  • Irina A. TolmachevaEmail author
  • Ekaterina V. Igosheva
  • Olga V. Savinova
  • Eugene I. Boreko
  • Vladimir F. Eremin
  • Victoria V. Grishko
Original Research


The effect of the synthetic modifications of the triterpenic A ring on the level of antiviral activity of triterpenic C3, C28 amides with a residue of racemic, (S), or (R)-enantiomeric 2-aminobutan-1-ol against herpes simplex viruses type I (HSV-I) and type II (HSV-II), as well as against human immunodeficiency virus type I (HIV-1) was investigated. The 2,3-secolupane racemic amide 5a was selected as a potent microbicidal agent with the highest virus inhibitory (against HSV-I and HSV-II) and virucidal (against HSV-1 and HIV-1) actions, the antiviral activity of which was provided by the (S)-enantiomeric conjugate 5b.


Betulinic acid Amides HIV HSV Antiviral activity Microbicides 



This research was financially supported by the Government of Perm Region (project Nr. С-26/056) and by the State Contractual Order Nr. AAAA-A18-118030790037-7.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

44_2019_2401_MOESM1_ESM.docx (9.5 mb)
Supplementary Data


  1. Baltina LA, Flekhter OB, Nigmatullina LR, Boreko EI, Pavlova NI, Nikolaeva SN, Savinova OV, Tolstikov GA (2003) Lupane triterpenes and derivatives with antiviral activity. Bioorg Med Chem Lett 13:3549–3552CrossRefGoogle Scholar
  2. Bednarczyk-Cwynar B, Günther A (2017) Advances in chemistry and pharmacology of triterpenoid synthetic dimers. Curr Med Chem 24(20):2205–2240CrossRefGoogle Scholar
  3. Chamoun-Emanuelli AM, Bobardt M, Moncla B, Mankowski MK, Ptak RG, Gallay P, Chena Z (2014) Evaluation of PD 404,182 as an anti-HIV and anti-herpes simplex virus microbicide. Antimicrob Agents Chemother 58:687–697CrossRefGoogle Scholar
  4. Chawla A, Wang C, Patton C, Murray M, Punekar Y, de Ruiter A, Steinhart C (2018) A Review of long-term toxicity of antiretroviral treatment regimens and implications for an aging population. Infect Dis Ther 7:183–185CrossRefGoogle Scholar
  5. Coric P, Turcaud S, Souquet F, Briant L, Gay B, Royer J, Chazal N, Bouaziz S (2013) Synthesis and biological evaluation of a new derivative of bevirimat that targets the Gag CA-SP1 cleavage site. Eur J Med Chem 62:453–465CrossRefGoogle Scholar
  6. Csuk R (2014) Betulinic acid and its derivatives: a patent review (2008−2013). Expert Opin Ther Pat 24:913–923CrossRefGoogle Scholar
  7. Das Neves J, Sarmento B (2014) Drug delivery and development of anti-HIV microbicides. Pan Stanford Publishing, Singapore, p 706CrossRefGoogle Scholar
  8. Dobrikov GM, Valcheva V, Stoilova-Disheva M, Momekov G, Tzvetkova P, Dimitrov V (2012) Synthesis and in vitro antimycobacterial activity of compounds derived from (R)- and (S)-2-amino-1-butanol—The crucial role of the configuration. Eur J Med Chem 48:45–56CrossRefGoogle Scholar
  9. Evers M, Poujade C, Soler F, Ribeill Y, James C, Lelie’vre Y, Gueguen J-C, Reisdorf D, Morize I, Pauwels R, De Clercq E, He´nin Y, Bousseau A, Mayaux J-F, Le Pecq J-B, Dereu N (1996) Betulinic acid derivatives: a new class of human immunodeficiency virus type 1 specific inhibitors with a new mode of action. J Med Chem 39:1056–1068CrossRefGoogle Scholar
  10. Flekhter OB, Boreko EI, Nigmatullina LR, Pavlova NI, Medvedeva NI, Nikolaeva SN, Tret’yakova EV, Savinova OV, Baltina LA, Karachurina LT, Galin FZ, Zarudii FS, Tolstikov GA (2004) Synthesis and pharmacological activity of acylated betulonic acid oxides and 28-oxo-allobetulone. Pharm Chem J 38:148–152CrossRefGoogle Scholar
  11. Galayko NV, Tolmacheva IA, Grishko VV, Volkova LV, Perevozchikova EN, Pestereva SA (2010) Antiviral activity of 2,3-secotriterpenic hydrazones of the lupane and 19β,28-epoxy-18α-oleanane types. Rus J Bioorg Chem 36:516–521CrossRefGoogle Scholar
  12. Galaiko NV, Tolmacheva IA, Igosheva EV, Savinova OV, Grishko VV (2018) Addition of cyanoethyl groups to ring A of triterpenoids. Chem Nat Compd 54:305–309CrossRefGoogle Scholar
  13. Gordts SC, Férir G, D’huys T, Petrova MI, Lebeer S, Snoeck R, Andrei G, Schols D (2015) The low-cost compound lignosulfonic acid (LA) exhibits broad-spectrum anti-HIV and anti-HSV activity and has potential for microbicidal applications. PLOS One 10(7):e0131219CrossRefGoogle Scholar
  14. Grishko VV, Galaiko NV, Tolmacheva IA, Kucherov II, Eremin VF, Boreko EI, Savinova OV, Slepukhin PA (2014) Functionalization, cyclization and antiviral activity of A-secotriterpenoids. Eur J Med Chem 83:601–608CrossRefGoogle Scholar
  15. Jin F, Prestage GP, Mao L, Kippax SC, Pell CM, Donovan B, Templeton DJ, Taylor J, Mindel A, Kaldor JM, Grulich AE (2006) Transmission of herpes simplex virus types 1 and 2 in a prospective cohort of HIV-negative gay men: the health in men study. J Infect Dis 194(5):561–570CrossRefGoogle Scholar
  16. Kaminska T, Kaczor J, Rzeski W, Wejksza K, Kandefer-Szerszen M, Witek M (2004) A comparison of the antiviral activity of three triterpenoids isolated from Betula alba bark. Ann Univ Mariae Curie-Sklodowska, Sect C Biol 59:7–13Google Scholar
  17. Kashiwada Y, Hashimoto F, Cosentino LM, Chen C-H, Garrett PE, Lee K-H (1996) Betulinic acid and dihydrobetulinic acid derivatives as potent anti-HIV agents. J Med Chem 39:1016–1017CrossRefGoogle Scholar
  18. Kim DS, Chen Z, Van Tuyen N, Pezzuto JM, Qiu S, Lu ZZ (1997) A concise semi-synthetic approach to betulinic acid from betulin. Synth Commun 27:1607–1612CrossRefGoogle Scholar
  19. Kizima L, Rodrı´guez A, Kenney J, Derby N, Mizenina O, Menon R, Seidor S, Zhang S, Levendosky K, Jean-Pierre N, Pugach P, Villegas G, Ford BE, Gettie A, Blanchard J, Piatak Jr M, Lifson JD, Paglini G, Teleshova N, Zydowsky TM, Robbiani M, Fernández-Romero JA (2014) A potent combination microbicide that targets SHIV-RT, HSV-2 and HPV. PLOS ONE 9(4):e94547CrossRefGoogle Scholar
  20. Konysheva AV, Tolmacheva IA, Savinova OV, Boreko EI, Grishko VV (2017) Regioselective transformation of the cyano group of triterpene α,β-alkenenitriles. Chem Nat Compd 53:687–690CrossRefGoogle Scholar
  21. Lee K-H (2010) Discovery and development of natural product-derived chemotherapeutic agents based on a medicinal chemistry approach. J Nat Prod 73:500–516CrossRefGoogle Scholar
  22. Looker KJ, Elmes JAR, Gottlieb SL, Schiffer JT, Vickerman P, Turner KME, Boily M-C (2017) Effect of HSV-2 infection on subsequent HIV acquisition: an updated systematic review and meta-analysis. Lancet Infect Dis 17(12):1303–1316CrossRefGoogle Scholar
  23. Martinez J, Coplan P, Wainberg MA (2006) Is HIV drug resistance a limiting factor in the development of anti-HIV NNRTI and NRTI-based vaginal microbicide strategies? Antivir Res 71:343–350CrossRefGoogle Scholar
  24. Pereslavtseva AV, Tolmacheva IA, Slepukhin PA, El’tsov OS, Kucherov II, Eremin VF, Grishko VV (2014) Synthesis of A-pentacyclic triterpene α,β-alkenenitriles. Chem Nat Compd 49:1059–1066CrossRefGoogle Scholar
  25. Pialoux G, Delaugerre C, Cotte L, Raffi F, Cua E, Molina J-M (2016) Pre-exposure prophylaxis: a useful tool to prevent human immunodeficiency virus infection? Clin Microbiol Infect 22:757–767CrossRefGoogle Scholar
  26. Pokorny J, Borková L, Urban M (2018) Click reactions in chemistry of triterpenes—advances towards development of potential therapeutics. Curr Med Chem 25:1–23CrossRefGoogle Scholar
  27. Salehi B, Kumar NVA, Sener B, Sharifi-Rad M, Kılıç M, Mahady GB, Vlaisavljevic S, Iriti M, Kobarfard F, Setzer WN, Ayatollahi SA, Ata A, Sharifi-Rad J (2018) Medicinal plants used in the treatment of human immunodeficiency virus. Int J Mol Sci 19:E1459CrossRefGoogle Scholar
  28. Samoshina NF, Denisenko MV, Denisenko VA, Uvarova NI (2003) Synthesis of glycosides of lupane-type triterpene acids. Chem Nat Compd 39:575–582CrossRefGoogle Scholar
  29. Soler F, Poujade C, Evers M, Carry J-C, He´nin Y, Bousseau A, Huet T, Pauwels R, De Clercq E, Mayaux J-F, Le Pecq J-B, Dereu N (1996) Betulinic acid derivatives: a new class of specific inhibitors of human immunodeficiency virus type 1 entry. J Med Chem 39:1069–1083CrossRefGoogle Scholar
  30. Sosnik A, Chiappetta DA, Carcaboso ÁM (2009) Drug delivery systems in HIV pharmacotherapy: what has been done and the challenges standing ahead. J Control Release 138:2–15CrossRefGoogle Scholar
  31. Sun I-C, Wang H-K, Kashiwada Y, Shen J-K, Cosentino LM, Chen C-H, Yang L-M, Lee K-H (1998) Anti-AIDS Agents. 34. Synthesis and structure-activity relationships of betulin derivatives as anti-HIV agents. J Med Chem 41:4648–4657CrossRefGoogle Scholar
  32. Tolmacheva IA, Galaiko NV, Igosheva EV, Konysheva AV, Nazarov AV, Krainova GF, Gorbunova MN, Boreko EI, Eremin VF, Grishko VV (2017) Synthesis and transformations of 2,3-secotriterpene derivatives of betulin. In: Kutchin AV, Shishkina LN, Weisfeld LI eds. Chemistry and technology of plant substances. Chemical and biochemical aspects. Apple Academic Press, Toronto, New Jersey, p 3–26CrossRefGoogle Scholar
  33. Tolmacheva IA, Grishko VV, Boreko EI, Savinova OV, Pavlova NI (2009) Synthesis and antiviral activity of 2,3-seco-derivatives of betulonic acid. Chem Nat Compd 45:673–676CrossRefGoogle Scholar
  34. Tolmacheva IA, Igosheva EV, Savinova OV, Boreko EI, Grishko VV (2014) Synthesis and antiviral activity of C-3(C-28)-substituted 2,3-seco-triterpenoids. Chem Nat Compd 49:1050–1058CrossRefGoogle Scholar
  35. Tolmacheva IA, Igosheva EV, Vikharev YB, Grishko VV, Savinova OV, Boreko EI, Eremin VF (2013) Synthesis and biological activity of mono and diamides of 2,3-secotriterpene acids. Rus J Bioorg Chem 39:186–193CrossRefGoogle Scholar
  36. Tolmacheva IA, Nazarov AV, Maiorova OA, Grishko VV (2008) Synthesis of lupane and 19β,28-epoxy-18α-oleanane 2,3-seco-derivatives based on betulin. Chem Nat Compd 44:606–611CrossRefGoogle Scholar
  37. Xiao S, Tian Z, Wang Y, Si L, Zhang L, Zhou D (2018) Recent progress in the antiviral activity and mechanism study of pentacyclic triterpenoids and their derivatives. Med Res Rev 38:951–976CrossRefGoogle Scholar
  38. Zhou M, Zhang R-H, Wang M, Xu G-B, Liao S-G (2017) Prodrugs of triterpenoids and their derivatives. Eur J Med Chem 131:222–236CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Irina A. Tolmacheva
    • 1
    Email author
  • Ekaterina V. Igosheva
    • 1
  • Olga V. Savinova
    • 2
  • Eugene I. Boreko
    • 2
  • Vladimir F. Eremin
    • 2
  • Victoria V. Grishko
    • 1
  1. 1.Institute of Technical Chemistry, Perm Federal Scientific Centre, Ural BranchRussian Academy of SciencesPermRussia
  2. 2.The Republican Research and Practical Center for Epidemiology and MicrobiologyMinskRepublic of Belarus

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