216 F. L. HORSFALL, JR. 



benzenoid ring was not especially important. However, conversion of 

 certain methyl benzimidazoles, not containing halogen substituents, 

 glycosides including ribofuranosides served to eliminate inhibitory 

 activity. 



The high activity of /3-D-ribofuranosides depends not only on the number of 

 halogen substituents in the benzenoid ring but also on the nature of the 

 carbohydrate moiety. Conversion of a dichloro derivative to the ribopyrano- 

 side failed to increase activity and conversion to the arabino-, galacto-, or 

 glucopyranoside caused a decrease in activity (Tamm et al., 1954). Moreover, 

 a-linked ribofuranosides were much less active than the corresponding 

 /S-linked derivatives. For the highest inhibitory activity against influenza 

 virus, which contains RNA, the carbohydrate moiety must not only be 

 ribose but ribofuranose in ^-linkage (Tamm, 1958). The structure-activity 

 relationships suggest that the most potent compounds interfere with RNA 

 synthesis directly, not with the activities of vitamin B 12 . 



Similar conclusions have been reached in comparable studies with 

 polio virus (Tamm and Nemes, 1957), which also contains RNA. The 

 most active inhibitors against this agent were /3-linked ribofuranosides. 

 Any departure from the /3-D-ribofuranose structure in the carbo- 

 hydrate moiety of the benzimidazole glycoside results in reduced 

 inhibitory activity against both polioviruses and influenza viruses (Tamm, 

 1958). 



In sharp contrast to the results secured with RNA-containing viruses 

 were those obtained with vaccinia virus (Tamm and Overman, 1957), which 

 contains DNA (Hoagland et al., 1940; Peters and Stoeckenius, 1954). 

 Conversion of chloro benzimidazoles to corresponding /3-D-ribofuranosides 

 did not increase inhibitory activity against this virus. Recently, Allfrey 

 (1958) demonstrated that a ^3-D-ribofuranoside (DRB), discussed in an earlier 

 section, which markedly interferes with RNA synthesis (Tamm, 1957; 

 Allfrey et al., 1957), does not inhibit the synthesis of DNA. 



Although it seems clear that the effectiveness of /3-D-ribofuranosides of 

 chloro benzimidazoles as inhibitors of virus multiplication reflects the nature 

 of the nucleic acid in the virus particle, it is becoming apparent that 

 other factors, not yet fully understood, may also be important (Tamm, 

 1958). 



In addition to the effects of glycosides of benzimidazoles on RNA synthesis, 

 those of certain compounds on protein synthesis may contribute to inhibition 

 of multiplication. As described in a preceding section, an a-D-arabinopyrano- 

 side of chloro benzimidazole (DAB), although not highly potent as an inhibitor 

 of influenza or poliovirus, is effective throughout the whole of the latent 

 period of the latter virus. This compound interferes with both RNA and 

 protein synthesis (Nemes and Tamm, 1958). 



