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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Several 8-substituted derivatives of guanosine 3 ',5'-cyclic phosphate (cGMP), inosine 3'.5 '-cyclic phosphate (cIMP), and xanthosine 3 ',5 '-cyclic phosphate (cXMP) were synthesized and their biochemical properties compared to corresponding 8-substituted adenosine 3 ',5 '-cyclic phosphate (CAMP) derivatives. cGMP was brominated to give 8bromo-cGMP which was subsequently used to synthesize ciri nucleophilic reactions, %hydroxy-, 8-dimethylamino-, 8methylamino-, 8-benzylamino-, 8-p-chlorophenylthio-, 8benzylthio-, and 8-methylthio-cGMP. Deamination of cGMP and 8-bromo-cGMP gave cXMP and 8-bromo-cXMPj respectively. were prepared by deamination of the respective 8-substituted CAMP. Hydrogenation of 8-azido-cIMP gave 8-amino-cIMP. Thiation of 8-bromo-cIMP gave 8-thio-cIMP.The substituted cGMP derivatives were specific for lobster rnuscle cGMP-dependent protein kinase whereas the 8-substituted cAMP derivatives were specific for bovine brain

Various derivatives of adenosine 3',5'-cyclic phosphate, most notably vV^'-O-dibutyryl-cAMP1 and several 8-alkylthio-cAMP analogs (Free et al., 1972), have been shown to be more effective than cAMP itself in many whole cell systems (see reviews by Robison et Severson, 1971). Reasons for the low activity of cAMP might include the low permeability of cAMP across cell membranes and its intracellular or extracellular hydrolysis by cAMP phosphodiesterase. It has been proposed that 7V6,2'-0-dibutyryl-cAMP is both more rapidly transported across cell membranes and less rapidly hydrolyzed by the phosphodiesterase (Posternak et al., 1962; Robison et al., 1971). It has further been suggested that the acylated derivatives of cAMP

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