Synthesis and Antiviral Evaluation of N-Carboxamidine-Substituted Analogs of 1-β-D-Ribofuranosyl-1,2,4-triazole-3-carboxamidine Hydrochloride

Academic Article


  • Ten, hitherto unreported, analogues of l-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamidine hydrochloride (2a, ribamidine) and methyl carboximidate 5 have been synthesized. These include the N-cyano (2b), N-alkyl (2c-e), N-amino acid (2f-h), N,N′-disubstituted (6, 7a,b), and the N-methylated carboxamide (1f) analogues of ribavirin. In addition, a new facile synthesis of carboxamidine 2a was also developed. All compounds were evaluated for biological activity against the following RNA viruses: Punta Toro (PT) and sandfly fever (SF) viruses (bunyaviruses); Japanese encephalitis (JE), yellow fever (YF), and dengue-4 viruses (flaviviruses); parainfluenza type 3 (PIV3), respiratory syncytial virus (RSV), and measles viruses (paramyxoviruses); influenza A and influenza B viruses (orthomyxoviruses); Venezuelan equine encephalomyelitis virus (VEE, alpha virus); human immunodeficiency virus type-1 (HIV-1, lentivirus); the DNA-containing vaccinia (W) virus (poxvirus); and adeno type 5 (Ad5) viruses. All of the compounds except for 2b and 7a,b exhibited activity against the bunyaviruses such as that observed with 2a; however, higher ICjo values were generally observed. Glycine analogue 2f showed activity in PT-virus-infected mice in terms of increased survivors and decreased markers of viral pathogenicity. Carboxamidine 2a, carboximidate 5, and dimethyl amidine 6 exhibited activity against dengue type-4 virus. Monomethyl amidine 2c demonstrated activity against RSV, PIV3, and, to a lesser extent, influenza A and B. Activity of 2c generally required higher IC50 values than unsubstituted 2a. The latter exhibited hitherto unreported activity against RSV; therapeutic indices for 2a against RSV and PIV3 were >64 and >21. No substantial in vitro activity was observed for any of the compounds tested against Ad5, measles, JE, YF, VEE, or HIV-1. In addition, evidence is presented which argues in favor of a distinct antiviral mechanism of action for carboxamidines, e.g. 6, in contrast to a role as a carboxamide precursor. © 1992, American Chemical Society. All rights reserved.
  • Published In

    Digital Object Identifier (doi)

    Author List

  • Gabrielsen B; Ussery MA; See C; Huggins JW; Kefauver DF; Monath TP; Phelan MJ; Barthel-Rosa L; Chmurny GN; Schubert EM
  • Start Page

  • 3231
  • End Page

  • 3238
  • Volume

  • 35
  • Issue

  • 17