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

Article abstract of DOI:10.1021/jm00095a020

Ten, hitherto unreported, analogues of 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamidine hydrochloride (2a, ribamidine) and methyl carboxamidate 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 B viruses (orthomyxoviruses); Venezuelan equine encephalomyelitis virus (VEE, alphavirus); human immunodeficiency virus type-1 (HIV-1, lentivirus); the DNA-containing vaccina (VV) virus (poxvirus); and adeno type-5 (Ad5) viruses.All of the compounds except for 2a and 7a,b exhibited activity against the bunyaviruses such as that observed with 2a; however, higher IC50 values were generally observed.Glycine analogue 2f showed activity in PT-virus-infected mice in therms of increased survivors and descreased 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.