Carbodine, the carbocyclic analog of
cytidine, was found to possess significant
antiviral activity against influenza virus types A0/PR-8/34 and A2/Aichi/2/68 (Hong Kong) in vitro. The compound selectively inhibited PR-8 influenza virus-induced cytopathogenic effects in Madin-Darby canine kidney and inhibited Hong Kong influenza virus replication in primary rhesus monkey kidney cell cultures. The 50% minimum inhibitory concentration for inhibition of
human influenza type A viruses by
carbodine was approximately 2.6 microgram/ml (i.e., in the range of
antiviral potency of
ribavirin, but less potent than
amantadine hydrochloride in concomitant assays). The fact that
carbodine is metabolized to
carbodine triphosphate in mammalian cells makes interference with the viral
ribonucleic acid-dependent
ribonucleic acid polymerase reaction a likely possibility for its principal mode of action. The carbocyclic analogs of
uridine (the deamination product of
carbodine), 2'-deoxycytidine,
3'-deoxycytidine, N,N-dimethylcytidine, N-methylcytidine, and some related carbocyclic analogs of
pyrimidine nucleosides were inactive against PR-8 influenza virus in vitro. The combination of
carbodine plus
tetrahydrouridine was no more effective in vitro than
carbodine alone, thus indirectly indicating that deamination of
carbodine probably did not occur to a significant degree during the cell culture experiments. Although reproducibly active in vitro,
carbodine did not exhibit any efficacy against lethal influenza virus
infections in mice when administered by either the intraperitoneal or intranasal routes up to dose-limiting toxic levels.