Skip to main content
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1991 Apr;35(4):679–684. doi: 10.1128/aac.35.4.679

Antiviral activities of 5-ethynyl-1-beta-D-ribofuranosylimidazole-4- carboxamide and related compounds.

E De Clercq 1, M Cools 1, J Balzarini 1, R Snoeck 1, G Andrei 1, M Hosoya 1, S Shigeta 1, T Ueda 1, N Minakawa 1, A Matsuda 1
PMCID: PMC245078  PMID: 2069373

Abstract

A series of novel compounds, 5-alkynyl-1-beta-D-ribofuranosylimidazole-4- carboxamides, have been identified as broad-spectrum antiviral agents. 5-Ethynyl-1-beta-D-ribofuranosylimidazole-4- carboxamide (EICAR), the most potent congener of the group, showed antiviral potency about 10- to 100-fold greater than that of ribavirin. Similar in spectrum to ribavirin, EICAR was particularly active (50% inhibitory concentration, 0.2 to 4 micrograms/ml) against poxviruses (vaccinia virus), togaviruses (Sindbis and Semliki forest viruses), arenaviruses (Junin and Tacaribe viruses), reoviruses (reovirus type 1), orthomyxoviruses (influenza A and B viruses), and paramyxoviruses (parainfluenza virus type 3, measles virus, subacute sclerosing panencephalitis virus, and respiratory syncytial virus). EICAR was also cytostatic for rapidly growing cells (50% inhibitory concentration, 0.2 to 0.9 microgram/ml). EICAR inhibited vaccinia virus tail lesion formation at doses that were not toxic to the host. EICAR is a candidate antiviral drug for the treatment of pox-, toga-, arena-, reo-, orthomyxo, and paramyxovirus infections.

Full text

PDF
679

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Andrei G., De Clercq E. Inhibitory effect of selected antiviral compounds on arenavirus replication in vitro. Antiviral Res. 1990 Oct-Nov;14(4-5):287–299. doi: 10.1016/0166-3542(90)90009-v. [DOI] [PubMed] [Google Scholar]
  2. Baba M., Pauwels R., Balzarini J., Herdewijn P., De Clercq E., Desmyter J. Ribavirin antagonizes inhibitory effects of pyrimidine 2',3'-dideoxynucleosides but enhances inhibitory effects of purine 2',3'-dideoxynucleosides on replication of human immunodeficiency virus in vitro. Antimicrob Agents Chemother. 1987 Oct;31(10):1613–1617. doi: 10.1128/aac.31.10.1613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Boritzki T. J., Berry D. A., Besserer J. A., Cook P. D., Fry D. W., Leopold W. R., Jackson R. C. Biochemical and antitumor activity of tiazofurin and its selenium analog (2-beta-D-ribofuranosyl-4-selenazolecarboxamide). Biochem Pharmacol. 1985 Apr 1;34(7):1109–1114. doi: 10.1016/0006-2952(85)90617-3. [DOI] [PubMed] [Google Scholar]
  4. Browne M. J. Mechanism and specificity of action of ribavirin. Antimicrob Agents Chemother. 1979 Jun;15(6):747–753. doi: 10.1128/aac.15.6.747. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cools M., de Clercq E. Correlation between the antiviral activity of acyclic and carbocyclic adenosine analogues in murine L929 cells and their inhibitory effect on L929 cells S-adenosylhomocysteine hydrolase. Biochem Pharmacol. 1989 Apr 1;38(7):1061–1067. doi: 10.1016/0006-2952(89)90249-9. [DOI] [PubMed] [Google Scholar]
  6. De Cercq E., Luczak M. Fluoroimidazoles as antiviral agents and inhibitors of polynucleotide biosynthesis. Life Sci. 1975 Jul 15;17(2):187–194. doi: 10.1016/0024-3205(75)90502-0. [DOI] [PubMed] [Google Scholar]
  7. De Clercq E. Antiviral and antimetabolic activities of neplanocins. Antimicrob Agents Chemother. 1985 Jul;28(1):84–89. doi: 10.1128/aac.28.1.84. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. De Clercq E., Balzarini J., Torrence P. F., Mertes M. P., Schmidt C. L., Shugar D., Barr P. J., Jones A. S., Verhelst G., Walker R. T. Thymidylate synthetase as target enzyme for the inhibitory activity of 5-substituted 2'-deoxyuridines on mouse leukemia L1210 cell growth. Mol Pharmacol. 1981 Mar;19(2):321–330. [PubMed] [Google Scholar]
  9. De Clercq E., Descamps J., Verhelst G., Walker R. T., Jones A. S., Torrence P. F., Shugar D. Comparative efficacy of antiherpes drugs against different strains of herpes simplex virus. J Infect Dis. 1980 May;141(5):563–574. doi: 10.1093/infdis/141.5.563. [DOI] [PubMed] [Google Scholar]
  10. De Clercq E., Luczak M., Shugar D., Torrence P. F., Waters J. A., Witkop B. Effect of cytosine, arabinoside, iododeoxyuridine, ethyldeoxyuridine, thiocyanatodeoxyuridine, and ribavirin on tail lesion formation in mice infected with vaccinia virus. Proc Soc Exp Biol Med. 1976 Mar;151(3):487–490. doi: 10.3181/00379727-151-39241. [DOI] [PubMed] [Google Scholar]
  11. De Clercq E. S-adenosylhomocysteine hydrolase inhibitors as broad-spectrum antiviral agents. Biochem Pharmacol. 1987 Aug 15;36(16):2567–2575. doi: 10.1016/0006-2952(87)90533-8. [DOI] [PubMed] [Google Scholar]
  12. Drach J. C., Thomas M. A., Barnett J. W., Smith S. H., Shipman C., Jr Tritiated thymidine incorporation does not measure DNA synthesis in ribavirin-treated human cells. Science. 1981 May 1;212(4494):549–551. doi: 10.1126/science.7209549. [DOI] [PubMed] [Google Scholar]
  13. Dudycz L., Shugar D., Clercq E. D., Descamps J. Synthesis and determination of antiviral activity of the 2'(3')-O-methyl derivatives of ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide). J Med Chem. 1977 Oct;20(10):1354–1356. doi: 10.1021/jm00220a027. [DOI] [PubMed] [Google Scholar]
  14. Gilbert B. E., Knight V. Biochemistry and clinical applications of ribavirin. Antimicrob Agents Chemother. 1986 Aug;30(2):201–205. doi: 10.1128/aac.30.2.201. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Goswami B. B., Borek E., Sharma O. K., Fujitaki J., Smith R. A. The broad spectrum antiviral agent ribavirin inhibits capping of mRNA. Biochem Biophys Res Commun. 1979 Aug 13;89(3):830–836. doi: 10.1016/0006-291x(79)91853-9. [DOI] [PubMed] [Google Scholar]
  16. Hosoya M., Shigeta S., Nakamura K., De Clercq E. Inhibitory effect of selected antiviral compounds on measles (SSPE) virus replication in vitro. Antiviral Res. 1989 Sep;12(2):87–97. doi: 10.1016/0166-3542(89)90072-7. [DOI] [PubMed] [Google Scholar]
  17. Huffman J. H., Sidwell R. W., Khare G. P., Witkowski J. T., Allen L. B., Robins R. K. In vitro effect of 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (virazole, ICN 1229) on deoxyribonucleic acid and ribonucleic acid viruses. Antimicrob Agents Chemother. 1973 Feb;3(2):235–241. doi: 10.1128/aac.3.2.235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Jayaram H. N., Pillwein K., Nichols C. R., Hoffman R., Weber G. Selective sensitivity to tiazofurin of human leukemic cells. Biochem Pharmacol. 1986 Jun 15;35(12):2029–2032. doi: 10.1016/0006-2952(86)90737-9. [DOI] [PubMed] [Google Scholar]
  19. Kawana F., Shigeta S., Hosoya M., Suzuki H., De Clercq E. Inhibitory effects of antiviral compounds on respiratory syncytial virus replication in vitro. Antimicrob Agents Chemother. 1987 Aug;31(8):1225–1230. doi: 10.1128/aac.31.8.1225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kini G. D., Robins R. K., Avery T. L. Synthesis and antitumor activity of ribavirin imidates. A new facile synthesis of ribavirin amidine (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamidine hydrochloride). J Med Chem. 1989 Jul;32(7):1447–1449. doi: 10.1021/jm00127a008. [DOI] [PubMed] [Google Scholar]
  21. Kirsi J. J., North J. A., McKernan P. A., Murray B. K., Canonico P. G., Huggins J. W., Srivastava P. C., Robins R. K. Broad-spectrum antiviral activity of 2-beta-D-ribofuranosylselenazole-4-carboxamide, a new antiviral agent. Antimicrob Agents Chemother. 1983 Sep;24(3):353–361. doi: 10.1128/aac.24.3.353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Knight V., Gilbert B. Antiviral therapy with small particle aerosols. Eur J Clin Microbiol Infect Dis. 1988 Dec;7(6):721–731. doi: 10.1007/BF01975037. [DOI] [PubMed] [Google Scholar]
  23. Lowe J. K., Brox L., Henderson J. F. Consequences of inhibition of guanine nucleotide synthesis by mycophenolic acid and virazole. Cancer Res. 1977 Mar;37(3):736–743. [PubMed] [Google Scholar]
  24. Matsuda A., Minakawa N., Sasaki T., Ueda T. The design, synthesis and antileukemic activity of 5-alkynyl-1-beta-D-ribofuranosylimidazole-4-carboxamides. Chem Pharm Bull (Tokyo) 1988 Jul;36(7):2730–2733. doi: 10.1248/cpb.36.2730. [DOI] [PubMed] [Google Scholar]
  25. McCormick J. B., King I. J., Webb P. A., Scribner C. L., Craven R. B., Johnson K. M., Elliott L. H., Belmont-Williams R. Lassa fever. Effective therapy with ribavirin. N Engl J Med. 1986 Jan 2;314(1):20–26. doi: 10.1056/NEJM198601023140104. [DOI] [PubMed] [Google Scholar]
  26. Narang A. S., Vince R. 1,2,4-Triazole amino nucleosides. 1-beta-D-3'-Amino-3'-deoxyribofuranosyl-1,2,4-triazole-3-carboxamide and related nucleosides. J Med Chem. 1977 Dec;20(12):1684–1687. doi: 10.1021/jm00222a032. [DOI] [PubMed] [Google Scholar]
  27. Pauwels R., De Clercq E., Desmyter J., Balzarini J., Goubau P., Herdewijn P., Vanderhaeghe H., Vandeputte M. Sensitive and rapid assay on MT-4 cells for detection of antiviral compounds against the AIDS virus. J Virol Methods. 1987 Jun;16(3):171–185. doi: 10.1016/0166-0934(87)90002-4. [DOI] [PubMed] [Google Scholar]
  28. Pickering M. V., Witkowski J. T., Robins R. K. Synthesis of 1-(4-thio-beta-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide. J Med Chem. 1976 Jun;19(6):841–842. doi: 10.1021/jm00228a022. [DOI] [PubMed] [Google Scholar]
  29. Riley T. A., Larson S. B., Avery T. L., Finch R. A., Robins R. K. 1,2,4-Diazaphosphole nucleosides. Synthesis, structure, and antitumor activity of nucleosides with a lambda 3 phosphorus atom. J Med Chem. 1990 Feb;33(2):572–576. doi: 10.1021/jm00164a016. [DOI] [PubMed] [Google Scholar]
  30. Scholtissek C. Inhibition of influenza RNA synthesis by virazole (ribavirin). Arch Virol. 1976;50(4):349–352. doi: 10.1007/BF01317961. [DOI] [PubMed] [Google Scholar]
  31. Shigeta S., Konno K., Yokota T., Nakamura K., De Clercq E. Comparative activities of several nucleoside analogs against influenza A, B, and C viruses in vitro. Antimicrob Agents Chemother. 1988 Jun;32(6):906–911. doi: 10.1128/aac.32.6.906. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Sidwell R. W., Huffman J. H., Khare G. P., Allen L. B., Witkowski J. T., Robins R. K. Broad-spectrum antiviral activity of Virazole: 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide. Science. 1972 Aug 25;177(4050):705–706. doi: 10.1126/science.177.4050.705. [DOI] [PubMed] [Google Scholar]
  33. Snoeck R., Sakuma T., De Clercq E., Rosenberg I., Holy A. (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine, a potent and selective inhibitor of human cytomegalovirus replication. Antimicrob Agents Chemother. 1988 Dec;32(12):1839–1844. doi: 10.1128/aac.32.12.1839. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Srivastava P. C., Pickering M. V., Allen L. B., Streeter D. G., Campbell M. T., Witkowski J. T., Sidwell R. W., Robins R. K. Synthesis and antiviral activity of certain thiazole C-nucleosides. J Med Chem. 1977 Feb;20(2):256–262. doi: 10.1021/jm00212a014. [DOI] [PubMed] [Google Scholar]
  35. Srivastava P. C., Robins R. K. Synthesis and antitumor activity of 2-beta-D-ribofuranosylselenazole-4- carboxamide and related derivatives. J Med Chem. 1983 Mar;26(3):445–448. doi: 10.1021/jm00357a024. [DOI] [PubMed] [Google Scholar]
  36. Srivastava P. C., Streeter D. G., Matthews T. R., Allen L. B., Sidwell R. W. Synthesis and antiviral and antimicrobial activity of certain 1-beta-D-ribofuranosyl-4,5-disubstituted imidazoles. J Med Chem. 1976 Aug;19(8):1020–1026. doi: 10.1021/jm00230a009. [DOI] [PubMed] [Google Scholar]
  37. Streeter D. G., Witkowski J. T., Khare G. P., Sidwell R. W., Bauer R. J., Robins R. K., Simon L. N. Mechanism of action of 1- -D-ribofuranosyl-1,2,4-triazole-3-carboxamide (Virazole), a new broad-spectrum antiviral agent. Proc Natl Acad Sci U S A. 1973 Apr;70(4):1174–1178. doi: 10.1073/pnas.70.4.1174. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Witkowski J. T., Robins R. K., Khare G. P., Sidwell R. W. Synthesis and antiviral activity of 1,2,4-triazole-3-thiocarboxamide and 1,2,4-triazole-3-carboxamidine ribonucleosides. J Med Chem. 1973 Aug;16(8):935–937. doi: 10.1021/jm00266a014. [DOI] [PubMed] [Google Scholar]
  39. Wood S. G., Upadhya K. G., Dalley N. K., McKernan P. A., Canonico P. G., Robins R. K., Revankar G. R. Synthesis and biological activity of 5-thiobredinin and certain related 5-substituted imidazole-4-carboxamide ribonucleosides. J Med Chem. 1985 Sep;28(9):1198–1203. doi: 10.1021/jm00147a013. [DOI] [PubMed] [Google Scholar]
  40. Wray S. K., Gilbert B. E., Knight V. Effect of ribavirin triphosphate on primer generation and elongation during influenza virus transcription in vitro. Antiviral Res. 1985 Feb;5(1):39–48. doi: 10.1016/0166-3542(85)90013-0. [DOI] [PubMed] [Google Scholar]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES