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Virazole is a synthetic nucleoside active in tissue culture against at least 16 DNA and RNA viruses. Applied topically, it inhibits herpetic keratitis in rabbits and tail lesions induced by herpes, vaccinia, and vesicular stomatitis viruses in mice. Injected intraperitoneally into mice, it inhibits splenomegaly and hepatomegaly induced by Friend leukemia virus and respiratory infections caused by influenza A(O), A(2), and B viruses and parainfluenza 1 virus. infections is also effective.

The antiviral activity of the synthetic nucleoside, Virazole (1-io-D-ribofuranosyl-1,2,4-triazole-3-carboxamide), against measles virus in Vero cell cultures was substantially reversed by xanthosine, guanosine, and to a slightly lesser extent by inosine. Virazole 5'-phosphate was subsequently found to be a potent competitive inhibitor of inosine 5'-phosphate dehydrogenase (IMP: NAD + oxidoreductase, EC 1.2.1.14) isolated from Escherichia coli (Km = 1.8 X 10-' M) with a Ki of 2.7 X 10-7 M.Guanosine 5'-phosphate (GMP) was a competitive inhibitor of this enzyme with a Ki of 7.7 X 106 M. Virazole 5'-phosphate was similarly active against IMP dehydrogenase isolated from Ehrlich ascites tumor cells, with a Ki of 2.5 X 10-7 M. The Km for this enzyme was 1.8 X 10-6 M, and the Ki for GMP was 2.2 X 10-4 M. These results suggest that the antiviral activity of Virazole might be due to the inhibition of GMP biosynthesis in the infected cell at the step involving the conversion of IMP to xanthosine 5'-phosphate. This inhibition would consequently result in inhibition of the synthesis of vital viral nucleic acid.The synthesis and development of a broad spectrum antiviral agent has been a challenging task because of the intimate association of virus replication and biochemical processes of the host cell. In addition, such an agent must inhibit a step in the process of virus replication that is common to a wide variety of RNA and DNA viruses (1). The synthesis and broad spectrum antiviral activity of 1-i3-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (I, Virazole) have recently been reported (1,2).

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A general and stereospecific synthesis has been developed for the direct preparation of 2'-deoxy-/3-D-ribofuranosylpurine analogues including 2'-deoxyadenosine derivatives. The reaction of the sodium salt of 4-chloropyrrolo[2,3-if)pyrimidine (4) or 2,4-dichloropy rrolo [ 2,3-tf] pyrimidine (1) with l-chloro-2-deoxy-3,5-di-0-/Holuoyl-a-D-er>>r/¡ro-pentofuranose (25) provided the corresponding N-1,2'-deoxy-|8-D-ribofuranosyl blocked derivatives (5 and 2) which, on ammonolysis, gave 2'-deoxytubercidin (6) and 2-chloro-2'-deoxytubercidin (3), respectively, in good yield. This glycosylation also readily proceeds in the presence of a 2-methylthio group. Application of this glycosylation procedure to 4,6-dichloroimidazo[4,5-c]pyridine (10), 6-chloropurine ( 16), 2,6-dichloropurine ( 13), and 4-chloropyrazolo[ 3,4-t/] pyrimidine ( 19) gave 2-chloro-2'-deoxy-3-deazaadenosine ( 12), 2'-deoxyadenosine (18), 2-chloro-2'-deoxyadenosine (15), and 4-amino-l-(2-deoxy-/3-D-eryiAro-pentofuranosyl)pyrazolo-[3,4-t/] pyrimidine (21), respectively. Similarly, glycosylation and ammonolysis of 4,6-dichloro-1 /f-pyrrolo[3,2-c]pyridine ( 22) gave 4,6-dichloro-l-(2-deoxy-0-D-e/,>rAro-pentofuranosyl)pyrrolo[3,2-c]pyridine (24). This stereospecific attachment of the 2-deoxy-/3-D-ribofuranosyl moiety appears to be due to a Walden inversion at the C-l carbon of 25.

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The relative in vitro antiviral activities of three related nucleoside carboxamides, ribavirin (1-3-D-ribofuranosyl-1,2,4-triazole-3-carboxamide), tiazofurin (2-3-D-ribofuranosylthiazole-4-carboxamide), and selenazole (2-p-D-ribofuranosylselenazole-4-carboxamide), were studied against selected DNA and RNA viruses. Although the activity of selenazole against different viruses varied, it was significantly more potent than ribavirin and tiazofurin against all tested representatives of the families Paramyxoviridae (parainfluenza virus type 3, mumps virus, measles virus), Reoviridae (reovirus type 3), Poxviridae (vaccinia virus), Herpesviridae (herpes simplex virus types 1 and 2), Togaviridae (Venezuelan equine encephalomyelitis virus, yellow fever virus, Japanese encephalitis virus), Bunyaviridae (Rift Valley fever virus, sandfly fever virus [strain Sicilian], Korean hemorrhagic fever virus), Arenaviridae (Pichinde virus), Picornaviridae (coxsackieviruses B1 and B4, echovirus type 6, encephalomyocarditis virus), Adenoviridae (adenovirus type 2), and Rhabdoviridae (vesicular stomatitis virus). The antiviral activity of selenazole was also cell line dependent, being greatest in HeLa, Vero-76, and Vero E6 cells. Selenazole was relatively nontoxic for Vero, Vero-76, Vero E6, and HeLa cells at concentrations of up to 1,000 ,g/ml. The relative plating efficiency at that concentration was over 90%. The effects of selenazole on viral replication were greatest when this agent was present at the time of viral infection. The removal of selenazole from the medium of infected cells did not reverse the antiviral effect against vaccinia virus, but there was a gradual resumption of viral replication in cells infected with parainfluenza type 3 or herpes simplex virus type 1 (strain KOS). However, the antiviral activity of ribavirin against the same viruses was reversible when the drig was removed.