INHIBITION OF MULTIPLICATION 215 



number of viruses. In addition, they made closely correlated studies of the 

 damaging effects of the compounds by various means in a number of host 

 cell systems. 



These comprehensive investigations culminated in the synthesis of com- 

 pounds with greatly increased inhibitory potency which interfere with the 

 multiplication of influenza, mumps, vaccinia, and polioviruses. Certain of the 

 compounds developed are moderately selective and show high inhibitory 

 activity without a corresponding increase in host cell damage (Tamm, 1958). 

 As stated in an earlier section, one highly potent and selective compound, 

 DRB, has been found to interfere with the synthesis of RNA in the chorio- 

 allantoic membrane in vitro; another, DAB, has been demonstrated to inter- 

 fere with the synthesis of both RNA and protein in monkey kidney cells in 

 vitro. These findings provide a basis for an understanding of the biochemical 

 mechanisms of their inhibitory effects (Tamm, 1958). 



Benzimidazole is structurally related to adenine and is found as a part of 

 the vitamin B 12 molecule (Tamm et al., 1952). The compound was first shown 

 to have an inhibitory effect on vaccinia virus multiplication in tissue culture 

 (Thompson, 1947; Thompson et al., 1950). Later it was found to inhibit the 

 multiplication of Theiler's GD VII virus in tissue culture (Rafelson et al., 

 1950) and poliovirus, type 2, in tissue culture (Brown, 1952). It had a 

 relatively small effect on experimental poliomyelitis in monkeys and no 

 inhibitory effect on the disease in mice (Brown et al., 1953). 



Systematic alteration of the structure of benzimidazole by substitution of 

 alkyl radicals at various positions in one or both rings markedly affected 

 inhibitory activity against influenza B virus multiplication in the chorio- 

 allantoic membrane in vitro (Tamm et al., 1953b). Both the position and the 

 nature of substituent groups appeared to be of decisive importance. The most 

 marked increases in inhibitory activity were achieved by the most extensive 

 substitution in either ring. Among the more potent compounds were the 2, 4, 

 5, 6, 7-pentamethyl, the 5, 6-diethyl, and the 2-ethyl-5-methyl derivatives, 

 two of which caused 75 % inhibition at approximately 200 \iM concentra- 

 tions. Further extension of these studies showed that chloro-substituted 

 benzimidazoles were 2 to 3 times more active than corresponding methyl 

 derivatives (Tamm et al., 1954). 



Recognizing that the 5, 6-dimethylbenzimidazole moiety in vitamin B 12 

 and the adenine and guanine moieties in nucleic acids are linked to pentoses 

 Tamm et al. (1954) undertook the synthesis and evaluation of a series of 

 N-glycosides of variously substituted benzimidazoles. It was found (Tamm 

 et al., 1954, 1956; Tamm, 1954b, 1956b) in all cases studied, that the /3-d- 

 ribofuranoside was more active than the corresponding halogenated ben- 

 zimidazole not containing the ribofuranosyl moiety. With the /3-D-ribo- 

 furanosides of 6 halogen derivatives, the type of halogen substituent in the 



