Benzimidazole derivatives: new enhancers of influenza virus multiplication.
The enhancing activity of 5-methyl-2-D-ribobenzimidazole on influenza B (Lee) virus yield in chorioallantoic membranes from 10-day old embryonated eggs was compared with that of eight other polyhydroxyalkyl-benzimidazoles. No marked differences in activity were noted with the following six derivatives: 5,6-dimethyl-2-D-ribo; 2-D-gluco; 5-methyl-2-D-gluco; 5,6-dimethyl-2-D-gluco; 5-methyl-2-D-galacto; and 5-methyl-2-L-rhamno. None caused morphological damage to the membranes at a concentration of 3.5 mM. The solubility of the 5-methyl-2-D-arabo and 5-methyl-2-D-manno derivatives was too low to permit quantitative comparisons, but both were active and nontoxic at a concentration of 1.75 mM. 5-Hydroxy-1-methylbenzimidazole and 5-methoxy-1-methylbenzimidazole are more active than 5-methyl-2-D-ribobenzimidazole both with respect to specific activity and maximal enhancement at the highest tolerated dose. The hydroxyl substituent is superior to the methoxyl grouping. Substitution at position 5 is superior to substitution at position 6 with respect to the tolerated dose level and therefore the maximal effect obtainable, but the 6-hydroxy-1-methyl derivative showed the highest specific activity. 5-Methoxy-1-methylbenzimidazole increases the yield to a comparable extent as measured by infectivity and hemagglutination titrations. The responses of membranes from individual chicken embryos to the enhancing action of 5-methoxy-1-methylbenzimidazole and 5-methyl-2-D-ribobenzimidazole are similar. 5-Methoxy-1-methylbenzimidazole restores the capacity of membranes from older chicken embryos to produce a large amount of virus after a small inoculum. This derivative increases the yield of virus in membranes treated before infection only. Maximal enhancement is obtained with prolonged treatment, starting before, and continuing after infection. 5-Methoxy-1-methyl-benzimidazole increases the yield of virus from COFAL-negative embryos in which the control yield is very low. Combined treatment with moderate doses of 5-methoxy-1-methylbenzimidazole and 5-methyl-2-D-ribobenzimidazole gives an additive effect.
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology* / Q000633:toxicity; D002642:Chick Embryo; D046508:Culture Techniques; D005321:Extraembryonic Membranes / Q000187:drug effects; D006027:Glycosides / Q000494:pharmacology / Q000633:toxicity; D009975:Orthomyxoviridae / Q000254:growth & development*; D012266:Ribose / Q000494:pharmacology / Q000633:toxicity; D014776:Virus Cultivation; D014779:Virus Replication / Q000187:drug effects*
D001562:Benzimidazoles; D006027:Glycosides; D012266:Ribose