The synthesis and antiviral activity against yellow fewer virus of 2-(4,6-di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-(alkyl, aryl)hydrazine-1-carbothioamides




1,3,5-triazine; carbothioamides; yellow fever; antiviral activity; cytotoxicity


Aim. To synthesize 2-(4,6-di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-(alkyl, aryl)hydrazine-1-carbothioamides and study their antiviral activity against yellow fever virus (YFV).

Results and discussion. The target 2-(4,6-di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-(alkyl, aryl)hydrazine-1-carbothioamides were obtained in three-step format from cyanuric chloride in good to high yields. The carbothioamides synthesized were estimated to possess the antiviral activity against YFV. The results obtained indicate that most of the compounds studied show the inhibitory activity against YFV in concentrations ≤10 μg/mL. For the most active substances, EC90 was in the range of 0.06 – 2.2 μg/mL. Good effective concentration values were accompanied by low levels of cytotoxicity resulting in excellent selectivity index values. The data obtained also indicate that the presence of an alkyl substituent in ortho-position of the N-aryl fragment is crucial for an effective inhibition of YFV growth.

Experimental part. 2-(4,6-Di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-(alkyl, aryl)hydrazine-1-carbothioamides were synthesized starting from cyanuric chloride in three steps by its successive interaction with two equivalents of pyrrolidine, hydrazine and a series of alkyl-/arylisothiocyanates. The antiviral and cytotoxic activities of the target carbothioamides were studied in the Southern Research Institute (SRI, Birmingham, Alabama) by the viral cytopathic effect reduction assay and the virus yield reduction assay.

Conclusions. 2-(4,6-Di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-(alkyl, aryl)hydrazine-1-carbothioamides synthesized have been proven to be a promising class of compounds for treating such a severe viral disease as yellow fever.

Supporting Agency

  • The work was carried out according to the research plan of the Nizhyn Mykola Gogol State University on the topic “Synthesis of novel sulfur- and nitrogen-containing heterocyclic compounds and investigation of their practically useful properties” (the state registration No. 0115U005451).


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  1. Waggoner, J. J.; Rojas, A.; Pinsky, B. A.; Kraft, C. S. Yellow Fever Virus: Diagnostics for a Persistent Arboviral Threat. J. Clin. Microbiol. 2018, 56 (10), e00827-18.
  2. Monath, T. P.; Vasconcelos, P. F. C. Yellow fever. Journal of Clinical Virology 2015, 64, 160 – 173.
  3. Figueiredo-Mello, C.; Casadio, L. V. B.; Avelino-Silva, V. I.; Yeh-Li, H.; Sztajnbok, J.; Joelsons, D.; Antonio, M. B.; Pinho, J. R. R.; Malta, F. d. M.; Gomes-Gouvêa, M. S.; Salles, A. P. M.; Corá, A. P.; Moreira, C. H. V.; Ribeiro, A. F.; Nastri, A. C. d. S. S.; Malaque, C. M. S. A.; Teixeira, R. F. A.; Borges, L. M. S.; Gonzalez, M. P.; Junior, L. C. P.; Souza, T. N. L.; Song, A. T. W.; D’Albuquerque, L. A. C.; Abdala, E.; Andraus, W.; Martino, R. B. d.; Ducatti, L.; Andrade, G. M.; Malbouisson, L. M. S.; Souza, I. M. d.; Carrilho, F. J.; Sabino, E. C.; Levin, A. S. Efficacy of sofosbuvir as treatment for yellow fever: protocol for a randomised controlled trial in Brazil (SOFFA study). BMJ Open 2019, 9 (11), e027207.
  4. Bryant, J. E.; Holmes, E. C.; Barrett, A. D. T. Out of Africa: A Molecular Perspective on the Introduction of Yellow Fever Virus into the Americas. PLOS Pathogens 2007, 3 (5), e75.
  5. Chippaux, J.-P.; Chippaux, A. Yellow fever in Africa and the Americas: a historical and epidemiological perspective. Journal of Venomous Animals and Toxins Including Tropical Diseases 2018, 24 (1), 20.
  6. Chen, L. H.; Wilson, M. E. Yellow fever control: current epidemiology and vaccination strategies. Tropical Diseases, Travel Medicine and Vaccines 2020, 6 (1), 1.
  7. Bredenbeek, P. J.; Kooi, E. A.; Lindenbach, B.; Huijkman, N.; Rice, C. M.; Spaan, W. J. M. A stable full-length yellow fever virus cDNA clone and the role of conserved RNA elements in flavivirus replication. Journal of General Virology 2003, 84 (5), 1261 – 1268.
  8. Tao, D.; Barba-Spaeth, G.; Rai, U.; Nussenzweig, V.; Rice, C. M.; Nussenzweig, R. S. Yellow fever 17D as a vaccine vector for microbial CTL epitopes: protection in a rodent malaria model. Journal of Experimental Medicine 2005, 201 (2), 201 – 209.
  9. Bredenbeek, P. J.; Molenkamp, R.; Spaan, W. J. M.; Deubel, V.; Marianneau, P.; Salvato, M. S.; Moshkoff, D.; Zapata, J.; Tikhonov, I.; Patterson, J.; Carrion, R.; Ticer, A.; Brasky, K.; Lukashevich, I. S. A recombinant Yellow Fever 17D vaccine expressing Lassa virus glycoproteins. Virology 2006, 345 (2), 299 – 304.
  10. Franco, D.; Li, W.; Qing, F.; Stoyanov, C. T.; Moran, T.; Rice, C. M.; Ho, D. D. Evaluation of yellow fever virus 17D strain as a new vector for HIV-1 vaccine development. Vaccine 2010, 28 (35), 5676 – 5685.
  11. Stoyanov, C. T.; Boscardin, S. B.; Deroubaix, S.; Barba-Spaeth, G.; Franco, D.; Nussenzweig, R. S.; Nussenzweig, M.; Rice, C. M. Immunogenicity and protective efficacy of a recombinant yellow fever vaccine against the murine malarial parasite Plasmodium yoelii. Vaccine 2010, 28 (29), 4644 – 4652.
  12. Nogueira, R. T.; Nogueira, A. R.; Pereira, M. C. S.; Rodrigues, M. M.; Neves, P. C. d. C.; Galler, R.; Bonaldo, M. C. Recombinant Yellow Fever Viruses Elicit CD8+ T Cell Responses and Protective Immunity against Trypanosoma cruzi. PLOS ONE 2013, 8 (3), e59347.
  13. Thomas, R. E.; Lorenzetti, D. L.; Spragins, W.; Jackson, D.; Williamson, T. Active and passive surveillance of yellow fever vaccine 17D or 17DD-associated serious adverse events: Systematic review. Vaccine 2011, 29 (28), 4544 – 4555.
  14. Hayes, E. B. Is it time for a new yellow fever vaccine? Vaccine 2010, 28 (51), 8073 – 8076.
  15. Belsher, J. L.; Gay, P.; Brinton, M.; DellaValla, J.; Ridenour, R.; Lanciotti, R.; Perelygin, A.; Zaki, S.; Paddock, C.; Querec, T.; Zhu, T.; Pulendran, B.; Eidex, R. B.; Hayes, E. Fatal multiorgan failure due to yellow fever vaccine-associated viscerotropic disease. Vaccine 2007, 25 (50), 8480-8485.
  16. Pulendran, B.; Miller, J.; Querec, T. D.; Akondy, R.; Moseley, N.; Laur, O.; Glidewell, J.; Monson, N.; Zhu, T.; Zhu, H.; Staprans, S.; Lee, D.; Brinton, M. A.; Perelygin, A. A.; Vellozzi, C.; Brachman, P., Jr.; Lalor, S.; Teuwen, D.; Eidex, R. B.; Cetron, M.; Priddy, F.; del Rio, C.; Altman, J.; Ahmed, R. Case of Yellow Fever Vaccine-associated Viscerotropic Disease with Prolonged Viremia, Robust Adaptive Immune Responses, and Polymorphisms in CCR5 and RANTES Genes. The Journal of Infectious Diseases 2008, 198 (4), 500 – 507.
  17. Mendes, É. A.; Pilger, D. R. B. d.; Santos Nastri, A. C. d. S.; Malta, F. d. M.; Pascoalino, B. d. S.; Carneiro D’Albuquerque, L. A.; Balan, A.; Freitas, L. H. G. d.; Durigon, E. L.; Carrilho, F. J.; Rebello Pinho, J. R. Sofosbuvir inhibits yellow fever virus in vitro and in patients with acute liver failure. Annals of Hepatology 2019, 18 (6), 816 – 824.
  18. Guo, F.; Wu, S.; Julander, J.; Ma, J.; Zhang, X.; Kulp, J.; Cuconati, A.; Block, T. M.; Du, Y.; Guo, J.-T.; Chang, J.; Diamond, M. S. A Novel Benzodiazepine Compound Inhibits Yellow Fever Virus Infection by Specifically Targeting NS4B Protein. Journal of Virology 2016, 90 (23), 10774 – 10788.
  19. Furuta, Y.; Takahashi, K.; Shiraki, K.; Sakamoto, K.; Smee, D. F.; Barnard, D. L.; Gowen, B. B.; Julander, J. G.; Morrey, J. D. T-705 (favipiravir) and related compounds: Novel broad-spectrum inhibitors of RNA viral infections. Antiviral Research 2009, 82 (3), 95 – 102.
  20. MedecinsSans Frontieres. Yellow Fever Case Management OCG Protocol. DMED–OCG/01.2013. (accessed May 18, 2021).
  21. Monath, T. P. Treatment of yellow fever. Antiviral Research 2008, 78 (1), 116 – 124.
  22. Blotny, G. Recent applications of 2,4,6-trichloro-1,3,5-triazine and its derivatives in organic synthesis. Tetrahedron 2006, 62 (41), 9507 – 9522.
  23. Kosáry, J.; Kasztreiner, E.; Rablóczky, G.; Kürthy, M. Synthesis and cardiotonic activity of 2,4-diamino-1.3,5-triazines. Eur. J. Med. Chem. 1989, 24 (1), 97 – 99.
  24. Brzozowski, Z.; Sączewski, F.; Gdaniec, M. Synthesis, structural characterization and antitumor activity of novel 2,4-diamino-1,3,5-triazine derivatives. Eur. J. Med. Chem. 2000, 35 (12), 1053 – 1064.
  25. An, H.; Chamakura, V.; Chen, H.; Hong, Z. (Ribapharm Inc.). Unusual nucleoside libraries, compounds, and preferred uses as antiviral and anticancer agents. Patent WO2003051898, Jun 26, 2003.
  26. Kukla, M. J.; Heeres, J.; Janssen, P. A. J.; Ludovici, D. W.; Moereels, H. E. L. (Janssen Pharmaceutica NV). Substituted diamino-1,3,5-triazine derivatives. Eur. Patent EP0834507A1, Apr 08, 1998.
  27. De Corte, B.; De Jonge, M. R.; Heeres, J.; Janssen, P. A. J.; Kavash, R. W.; Koymans, L. M. H.; Kukla, M. J.; Ludovici, D. W.; Van Aken, K. J. A. 2,4-Disubstituted triazine derivatives. Int. Patent WO0027828A2, May 18, 2000.
  28. Mibu, N.; Yokomizo, K.; Yuzuriha, A.; Otsubo, M.; Kawaguchi, Y.; Sano, M.; Sakai, I.; Nakayama, K.; Zhou, J.-R.; Sumoto, K. Antiviral Activities of Some New 2,4,6-Trisubstituted 1,3,5-Triazines Having Alkoxy and/or Alkylamino Groups. Heterocycle 2017, 94 (9), 1653 – 1677.
  29. Yaguchi, Sh.; Koshimizu, I.; Yoshimi, H.; Matsuno, T.; Watanabe, T.; Tsuchida, Y.; Saitoh, K. (Zenyaku Kogyo Kabushiki Kaisha). Treatment of prostate cancer, melanoma or hepatic cancer. US Pat. 2007244110A1, Oct 18. 2007.
  30. CIBA LTD. New Triazines and process for preparing same. Pat. GB 942961, Nov 27, 1963.
  31. Демченко, А. М.; Барчина, О. І.; Суховєєв, В. В.; Смольський, О. С.; Курач, А. В. Синтез та антиоксидантні властивості похідних 2-R-(4,6-дипіролідин-1-ІЛ)-[1,3,5]-триазин-2-іл)-N-гідразинокарботіоамідів. Наукові записки Тер­нопільського національного педагогічного університету ім. Володимира Гнатюка. Сер. Хімія 2011, 18, 13 – 19.
  32. Smee, D. F.; Hurst, B. L.; Evans, W. J.; Clyde, N.; Wright, S.; Peterson, C.; Jung, K.-H.; Day, C. W. Evaluation of cell viability dyes in antiviral assays with RNA viruses that exhibit different cytopathogenic properties. Journal of Virological Methods 2017, 246, 51 – 57.
  33. Bacon, T. H.; Howard, B. A.; Spender, L. C.; Boyd, M. R. Activity of penciclovir in antiviral assays against herpes simplex virus. J. Antimicrob. Chemother. 1996, 37 (2), 303 – 313.




How to Cite

Moskalenko, O. V.; Barchina, O. I.; Tsyhankov, S. A.; Lega, D. A.; Fedchenkova, Y. A.; Demchenko, A. M. The Synthesis and Antiviral Activity Against Yellow Fewer Virus of 2-(4,6-di(pyrrolidin-1-Yl)-1,3,5-Triazin-2-Yl)-N-(alkyl, aryl)hydrazine-1-Carbothioamides. J. Org. Pharm. Chem. 2021, 19, 36-43.



Original Researches