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Synthesis, antiviral evaluation, molecular docking study and cytotoxicity of 5′-phosphorylated 1,2,3-triazolyl nucleoside analogues with thymine and 6-methyl uracil moieties

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Abstract

A comparative analysis of in vitro antiviral activity (in terms of the concentration of semi-maximal inhibition, IC50) against influenza virus A/PR/8/34 (H1N1) of a large series of parent 1,2,3-triazolyl nucleoside analogues (with uracil, thymine, 6-methyluracil, quinazoline-2,4-dione moieties as nucleic bases) and their prodrug forms with masked 5ʹ-phosphate groups (diethyl phosphate, diphenyl phosphate, phosphoramidate) and negatively charged H-phosphonate and monophosphate groups was carried out. Obtained structure-activity relationships were interpreted based on the assumption that the synthesized parent 1,2,3-triazolyl nucleoside analogues and their prodrug forms, by analogy with the literature data, are metabolized by cellular kinases to their active 5ʹ-triphosphate forms that inhibit the activity of viral RNA-dependent RNA polymerase (RdRp). A correlation was found between the experimental values of IC50 and the theoretical values of the binding energies of 5ʹ-triphosphate derivatives of the parent 1,2,3-triazolyl nucleoside analogues in the active site of RdRp.

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References

  1. Balzarini J. Metabolism and mechanism of antiretroviral action of purine and pyrimidine derivatives. Pharm World Sci. 1994;16:113–26. https://doi.org/10.1007/BF01880662

    Article  CAS  PubMed  Google Scholar 

  2. Pastuch-Gawołek G, Gillner D, Krol E, Walczak K, Wandzik I. Selected nucleos(t)ide-based prescribed drugs and their multi-target activity. Eur J Pharm. 2019;865:172747. https://doi.org/10.1016/j.ejphar.2019.172747

    Article  CAS  Google Scholar 

  3. Eyer L, Nencka R, De Clercq E, Seley-Radtke K, Ruzek D. Nucleoside analogs as a rich source of antiviral agents active against arthropod-borne flaviviruses. Antiviral Chem Chemother. 2018;26:1–28. https://doi.org/10.1177/2040206618761299

    Article  CAS  Google Scholar 

  4. Jordheim LP, Durantel D, Zoulim F, Dumontet C. Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases. Nat Rev Drug Discovery. 2013;12:447–64. https://doi.org/10.1038/nrd4010

    Article  CAS  PubMed  Google Scholar 

  5. Martin JC, Hitchcock MJM, Kaul S, Dunkle LM, Sterzycki RZ, Mansuri MM, et al. Comparative studies of 2′,3′-didehydro-2′3′-dideoxythymidine (d4T) with other pyrimidine nucleoside analogues. Ann NY Acad Sci. 1990;616:22–28. https://doi.org/10.1111/j.1749-6632.1990.tb17824.x

    Article  CAS  PubMed  Google Scholar 

  6. Gao WY, Agbaria R, Driscoll JS, Mitsuya H. Divergent anti-human immunodeficiency virus activity and anabolic phosphorylation of 2′,3′-dideoxynucleoside analogs in resting and activated human cells. J Biol Chem. 1994;269:12633–8. https://doi.org/10.1016/S0021-9258(18)99923-0

    Article  CAS  PubMed  Google Scholar 

  7. Stein DS, Moore KH. Phosphorylation of nucleoside analog antiretrovirals: a review for clinicians. Pharmacotherapy. 2001;21:11–34. https://doi.org/10.1592/phco.21.1.11.34439

    Article  CAS  PubMed  Google Scholar 

  8. Roy R, Depaix A, Périgaud C, Peyrottes S. Recent trends in nucleotide synthesis. Chem Rev. 2016;116:7854–97. https://doi.org/10.1021/acs.chemrev.6b00174

    Article  CAS  PubMed  Google Scholar 

  9. Kataev VE, Garifullin BF. Antiviral nucleoside analogs. Chem Heterocycl Comp. 2021;57:326–41. https://doi.org/10.1007/s10593-021-02912-8

    Article  CAS  Google Scholar 

  10. Li Y, Mao S, Hager MW, Becnel KD, Schinazi RF, Liotta DC. Synthesis and evaluation of 2ʹ-substituted cyclobutyl nucleosides and nucleotides as potential anti-HIV agents. Bioorg Med Chem Lett. 2007;17:3398–401. https://doi.org/10.1016/j.bmcl.2007.03.094

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Toti KS, Derudas M, Pertusati F, Sinnaeve D, Van den Broeck F, Margamuljana L, et al. Synthesis of an apionucleoside family and discovery of a prodrug with anti-HIV activity. J Org Chem. 2014;79:5097–112. https://doi.org/10.1021/jo500659e

    Article  CAS  PubMed  Google Scholar 

  12. Chien M, Anderson TK, Jockusch D, Tao C, Li X, Kumar S, et al. Nucleotide Analogues as Inhibitors of SARS-CoV-2 Polymerase, a Key Drug Target for COVID-19. J Proteome Res. 2020;19:4690–7. https://doi.org/10.1021/acs.jproteome.0c00392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Montgomery JA, Thomas HJ, Schaeffer HJ. Synthesis of potential anticancer agents. XXVIII. Simple esters of 6-mercaptopurine ribonucleotide. J Org Chem. 1961;26:1929–33. https://doi.org/10.1021/jo01065a058

    Article  CAS  Google Scholar 

  14. Wagner CR, Iyer VV, McIntee EJ. Pronucleotides:toward the in vivo delivery of antiviral and anticancer nucleotides. Med Res Rev. 2000;20:417–51. https://doi.org/10.1002/1098-1128(200011)20:6<417::aid-med1>3.0.co;2-z

    Article  CAS  PubMed  Google Scholar 

  15. Cahard D, McGuigan C, Balzarini J. Aryloxy phosphoramidate triesters as Pro-Tides. Mini Rev Med Chem. 2004;4:371–81. https://doi.org/10.2174/1389557043403936.

    Article  CAS  PubMed  Google Scholar 

  16. Mehellou Y, Balzarini J, McGuigan C. Aryloxy phosphoramidate triesters: a technology for delivering monophosphorylated nucleosides and sugars into cells. ChemMedChem. 2009;4:1779–91. https://doi.org/10.1002/cmdc.200900289

    Article  CAS  PubMed  Google Scholar 

  17. Singh US, Mulamoottil VA, Chu CK. 2′-Fluoro-6′-methylene carbocyclic adenosine and its phosphoramidate prodrug: A novel anti-HBV agent, active against drug-resistant HBVmutants. Med Res Rev. 2018;38:977–1002. https://doi.org/10.1002/med.21490

    Article  CAS  PubMed  Google Scholar 

  18. McGuigan C, Madela K, Aljarah M, Gilles A, Brancale A, Zonta N, et al. Design, synthesis and evaluation of a novel double pro-drug: INX-08189. A new clinical candidate for hepatitis C virus. Bioorg Med Chem Lett. 2010;20:4850–4. https://doi.org/10.1016/j.bmcl.2010.06.094

    Article  CAS  PubMed  Google Scholar 

  19. Mehellou Y, Rattan HS, Balzarini J. The ProTide prodrug technology: from the concept to the clinic. J Med Chem. 2018;61:2211–26. https://doi.org/10.1021/acs.jmedchem.7b00734

    Article  CAS  PubMed  Google Scholar 

  20. Wang G, Lim SP, Chen YL, Hunziker J, Rao R, Gu F, et al. Structure-activity relationship of uridine-based nucleoside phosphoramidate prodrugs for inhibition of dengue virus RNA-dependent RNA polymerase. Bioorg Med Chem Lett. 2018;28:2324–7. https://doi.org/10.1016/j.bmcl.2018.04.069

    Article  CAS  PubMed  Google Scholar 

  21. Schooley RT, Carlin AF, Beadle JR, Valiaeva N, Zhang XQ, Clark AE, et al. Rethinking Remdesivir: synthesis, antiviral activity, and pharmacokinetics of oral lipid prodrugs. Antimicrob Agents Chemother. 2021;65:e01155–21. https://doi.org/10.1128/AAC.01155-21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Seley-Radtke KL, Yates MK. The evolution of nucleoside analogue antivirals: A review for chemists and non-chemists. Part 1: Early structural modifications to the nucleoside scaffold. Antivir Res. 2018;154:66–86. https://doi.org/10.1016/j.antiviral.2018.04.004

    Article  CAS  PubMed  Google Scholar 

  23. Slusarczyk M, Serpi M, Pertusati F. Phosphoramidates and phosphonamidates (ProTides) with antiviral activity. Antivir Chem Chemother. 2018;26:1–31. https://doi.org/10.1177/2040206618775243

    Article  CAS  Google Scholar 

  24. Pruijssers AJ, Denison MR. Nucleoside analogues for the treatment of coronavirus infections. Curr Opinion Virology. 2019;35:57–62. https://doi.org/10.1016/j.coviro.2019.04.002

    Article  CAS  Google Scholar 

  25. Tatarinov DA, Garifullin BF, Belenok MG, Andreeva OV, Strobykina IYU, Shepelina AV, et al. The first 5′-phosphorylated 1,2,3-triazolyl nucleoside analogues with uracil and quinazoline-2,4-dione moieties. Synthesis and antiviral evaluation. Molecules. 2022;27:6214. https://doi.org/10.3390/molecules27196214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Andreeva OV, Garifullin BF, Zarybaev VV, Slita AV, Yesaulkova IL, Saifina LF, et al. Synthesis and biological evaluation of 1,2,3-triazolyl nucleoside analogues as potential antiviral agents against influenza virus A (H1N1) and coxsackievirus B4. Mol Diversity. 2021;25:473–90. https://doi.org/10.1007/s11030-020-10141-y

    Article  CAS  Google Scholar 

  27. Fan WQ, Katritzky AR 1,2,3-Triazoles. In: Katritzky AR, Rees CW, Scriven EFV, editors. Comprehensive Heterocyclic Chemistry. Oxford, UK; Pergamon; 1997. Vol. 4. p. 2-129.

  28. Alexandrova LA, Efremenkova OV, Andronova VL, Galegov GA, Solyev PN, Karpenko IL, et al. 5-(4-Alkyl-1,2,3-triazol-1-yl)methyl derivatives of 2’-deoxyuridine as inhibitors of viral and bacterial growth. Russ J Bioorg Chem. 2016;42:677–84. https://doi.org/10.1134/S1068162016050022

    Article  CAS  Google Scholar 

  29. Chatzileontiadou DSM, Parmenopoulou V, Manta S, Kantsadi AL, Kylindri P, Griniezaki M, et al. Triazole double-headed ribonucleosides as inhibitors of eosinophil derived neurotoxin. Bioorg Chem. 2015;63:152–65. https://doi.org/10.1016/j.bioorg.2015.10.007

    Article  CAS  PubMed  Google Scholar 

  30. Malin AA, Ostrovskii VA. Synthesis of thymidine derivatives as potential pharmaceuticals against HIV/AIDS infection. Russ J Org Chem. 2001;37:759–80. https://doi.org/10.1023/A:1012441026853

    Article  CAS  Google Scholar 

  31. Kowalinski E, Zubieta C, Wolkerstorfer A, Szolar OHJ, Ruigrok RWH, Cusack S. Structural analysis of specific metal chelating inhibitor binding to the endonuclease domain of influenza pH1N1 (2009) polymerase. PloS Pathog. 2012;8:e1002831. https://doi.org/10.1371/journal.ppat.1002831

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Jockusch S, Tao C, Li X, Anderson TK, Chien M, Kumar S, et al. A library of nucleotide analogues terminate RNA synthesis catalyzed by polymerases of coronaviruses that cause SARS and COVID-19. Antiviral Res. 2020;180:104857. https://doi.org/10.1016/j.antiviral.2020.104857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Jácome R, Campillo-Balderas JA, Ponce de León S, Becerra A, Lazcano A. Sofosbuvir as a potential alternative to treat the SARS-CoV-2 epidemic. Sci. Rep. 2020;10:9294. https://doi.org/10.1038/s41598-020-66440-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Das K, Aramini JM, Ma LC, Krug RM, Arnold E. Structures of influenza A proteins and insights into antiviral drug targets. Nature SMB. 2010;17:530–8. https://doi.org/10.1038/nsmb.1779

    Article  CAS  Google Scholar 

  35. Fudo S, Yamamoto N, Nukaga M, Odagiri T, Tashiro M, Hoshino T. Two distinctive binding modes of endonuclease inhibitors to the N‑terminal region of influenza virus polymerase acidic subunit. Biochemistry. 2016;55:2646–60. https://doi.org/10.1021/acs.biochem.5b01087

    Article  CAS  PubMed  Google Scholar 

  36. Lao J, Vanet A. A new strategy to reduce influenza escape: detecting therapeutic targets constituted of invariance groups. Viruses. 2017;9:38. https://doi.org/10.3390/v9030038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Luganini A, Terlizzi ME, Catucci G, Gilardi G, Maffei ME, Gribaudo G. The cranberry extract Oximacro® exerts in vitro virucidal activity against influenza virus by interfering with hemagglutinin. Front Microbiol. 2018;9:1826. https://doi.org/10.3389/fmicb.2018.01826.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Zhang W, Chen ST, He QY, Huang LQ, Li X, Lai XP, et al. Asprellcosides B of Ilex asprella Inhibits Influenza A virus infection by blocking the hemagglutinin- mediated membrane fusion. Front Microbiol. 2019;9:3325. https://doi.org/10.3389/fmicb.2018.03325

    Article  PubMed  PubMed Central  Google Scholar 

  39. Gamblin SJ, Haire LF, Russell RJ, Stevens DJ, Xiao B, Ha Y, et al. The structure and receptor binding properties of the 1918 influenza hemagglutinin. Science. 2004;303:1838–43. https://doi.org/10.1126/science.1093155

    Article  PubMed  Google Scholar 

  40. Berman H, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, et al. The protein data bank. Nucleic Acids Res. 2000;28:235–42. https://doi.org/10.1093/nar/28.1.235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Benton DJ, Wharton SA, Martin SR, McCauley JW. Role of neuraminidase in influenza A(H7N9) virus receptor binding. J Virol. 2017;91:e02293–16. https://doi.org/10.1128/JVI.02293-16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Dou D, Revol R, Östbye H, Wang H, Daniels R. Influenza A virus cell entry, replication, virion assembly and movement. Front Immunol. 2018;9:1581. https://doi.org/10.3389/fimmu.2018.01581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. D’Souza C, Kanyalkar M, Joshi M, Coutinho E, Srivastava S. Search for novel neuraminidase inhibitors: design, synthesis and interaction of oseltamivir derivatives with model membrane using docking, NMR and DSC methods. Biochim Biophys Acta Biomembr. 2009;1740:1740–51. https://doi.org/10.1016/j.bbamem.2009.04.014

    Article  CAS  Google Scholar 

  44. Herlambang SJ, Saleh R. Molecular docking investigation for Indonesian H274Y mutant neuraminidase type 1 with neuraminidase inhibitors. Am J Mol Biol. 2012;2:49–59. https://doi.org/10.4236/ajmb.2012.21006

    Article  CAS  Google Scholar 

  45. Le K, Tran D, Nguyen A, Le L. A screening of neuraminidase inhibition activities of isoquinolone alkaloids in Coptis chinensis using molecular docking and pharmacophore analysis. ACS Omega. 2020;5:30315–22. https://doi.org/10.1021/acsomega.0c04847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. van der Vries E, Collins PJ, Vachieri SG, Xiong X, Liu J, Walker PA, et al. H1N1 2009 pandemic influenza virus: resistance of the I223R neuraminidase mutant explained by kinetic and structural analysis. PLoS Pathog. 2012;8:e1002914. https://doi.org/10.1371/journal.ppat.1002914

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Trott O, Olson FJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J Comput Chem. 2010;31:455–61. https://doi.org/10.1002/jcc.21334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. HyperChem Professional 8.0 (2007). Hypercube, Inc. http://www.hyper .com/?tabid=360. Accessed 26 November 2022.

  49. O’Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR. Open babel: an open chemical toolbox. J Cheminform. 2011;3:33. https://doi.org/10.1186/1758-2946-3-33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are grateful to the Assigned Spectral-Analytical Centre of FRC Kazan Scientific Centre of RAS for technical assistance in research.

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Authors and Affiliations

  1. Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, Arbuzov str., 8, Kazan, 420088, Russian Federation

    Bulat F. Garifullin, Dmitry A. Tatarinov, Olga V. Andreeva, Mayya G. Belenok, Irina Yu. Strobykina, Leysan R. Khabibulina, Anna V. Shepelina, Alexandra D. Voloshina, Anna P. Lyubina, Liliya E. Saifina, Vyacheslav E. Semenov & Vladimir E. Kataev

  2. Kazan National Research Technological University, K. Marx str., 68, Kazan, 420015, Russian Federation

    Bulat F. Garifullin & Leysan R. Khabibulina

  3. Pasteur Institute of Epidemiology and Microbiology, Mira str., 14, Saint Petersburg, 197101, Russian Federation

    Vladimir V. Zarubaev, Alexander V. Slita & Alexandrina S. Volobueva

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  1. Bulat F. Garifullin
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Garifullin, B.F., Tatarinov, D.A., Andreeva, O.V. et al. Synthesis, antiviral evaluation, molecular docking study and cytotoxicity of 5′-phosphorylated 1,2,3-triazolyl nucleoside analogues with thymine and 6-methyl uracil moieties. Med Chem Res 32, 1770–1803 (2023). https://doi.org/10.1007/s00044-023-03112-z

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