Glycosides of chlorobenzimidazoles as inhibitors of polioviurs multiplication

Tamm, Igor; Nemes, Marjorie M.

doi:10.1016/0042-6822(57)90081-8

Cited by 24 publications

(15 citation statements)

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“…The present report concerns the virus inhibitory activity and selectivity of a series of benzimidazole and benzotriazole derivatives which have been studied with influenza B virus in the chorioallantoic membrane in vitro and with poliovirus type 2 in monkey kidney cell cultures. The results obtained confirm the earlier conclusion (1-3, 5, 8) that extensive substitution in either the benzenoid or the imidazole ring frequently gives compounds of very high virus inhibi-Tissue Cultures.--Cultures of chorioallantoi¢ membrane and of monkey kidney cells were similar to those used previously (4,7). A medium designated buffered glucosol (9) was used with the chorioallantoie membrane, and protein-free Eagle's medium (20) with monkey kidney cells.…”

Section: (From the Rockefeller Institute And The Merck Sharp And Dohsupporting

confidence: 83%

“…PLATES 70 TO 72 (Received for publication, December 9, 1950) Through studies of structure-activity relationships with benzimidazole derivatives and various viruses, compounds with interesting biological activities (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) have been obtained. In some instances, new biologically active derivatives were developed in the course of systematic attempts to increase, through structural alteration, the virus inhibitory activity or selectivity of action of existing compounds (3,5,8).…”

Section: (From the Rockefeller Institute And The Merck Sharp And Dohmentioning

confidence: 99%

“…In other instances, striking biological activities of derivatives were discovered unexpectedly (10,11,19). It should be emphasized that no direct inactivating effects on virus infectivity were found (2,6,7,13). Most of the derivatives inhibited (1-9, 12, 15), and some of them enhanced (10,11,18) virus multiplication; others had no effect.…”

Section: (From the Rockefeller Institute And The Merck Sharp And Dohmentioning

confidence: 99%

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Relationship Between Structure of Benzimidazole Derivatives and Selective Virus Inhibitory Activity

Tamm

Bablanian

Nemes

et al. 1961

The Journal of Experimental Medicine

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The virus inhibitory activity and selectivity of certain benzimidazole, benzotriazole, and naphthimidazole derivatives were determined with influenza B and polio type 2 viruses. Among the sixty-five compounds examined, several were highly active inhibitors of influenza B virus multiplication in the chorioallantoic membrane in vitro. The following compounds, listed in order of increasing inhibitory activity, were more than 100 times as active as benzimidazole: 5-(4'-toluenesulfonamido)-benzimidazole, 5-hydroxybenzotriazole-4-carboxy-α-naphthylamide, 4,5,6-trichlorobenzotriazole, 5-(3',4'-dichlorobenzenesulfonamido)-benzimidazole, 5-(3',4'-dichlorobenzenesulfonamido) - 1 - (3'',4'' - dichlorobenzenesulfonyl)-benzimidazole, 4-(p-chlorophenylazo)-5-hydroxybenzotriazole, and 4,5,6,7-tetrachlorobenzotriazole. However, none showed high selectivity. Of the sixty-five compounds studied with influenza virus, twenty-five were also examined with poliovirus type 2 in monkey kidney cells in vitro. Included in this group were five of the seven most active inhibitors of influenza virus, listed above. All five were more than 100 times as active in inhibiting poliovirus multiplication as the reference compound. In addition to these, two other compounds were highly active: 2-(α-hydroxybenzyl)-benzimidazole (HBB), and 2-(α-hydroxybenzyl)-5-chlorobenzimidazole, with relative inhibitory activities of 78 and 130, respectively. These two compounds, and the much less active 5,6-dichloro derivative of HBB, were the only ones which showed no, or only slight, toxic effects on cells at concentrations sufficient to cause considerable inhibition of poliovirus multiplication. Furthermore, HBB and the 5-chloro derivative were the only compounds which caused significant inhibition of the cytopathic effects of poliovirus. HBB, and its 5-chloro and 5,6-dichloro derivatives had no effect on the multiplication of influenza B virus in the chorioallantoic membrane. In addition, HBB failed to inhibit influenza B virus multiplication and cytopathic effects in monkey kidney cells. Inhibition of poliovirus-induced cell damage by HBB was characterized by the following features: the curves relating reduction in virus yield or cytopathic effects to concentration of the compound followed an approximately parallel course; somewhat higher concentrations were required to inhibit virus-induced cell damage than to reduce virus yield. HBB suppressed viral cytopathic effects for a period of time which varied directly with the concentration of compound, and inversely with the size of virus inoculum. The development of virus-induced cell damage in treated cultures on prolonged incubation was not due to inactivation of HBB. The inhibitory effect of HBB on virus-induced cell damage was reversible by removal of the compound. HBB inhibited viral cytopathic effects when given during the exponential increase phase in virus multiplication. Inhibition of virus-induced cell damage by HBB was demonstrated by photomicrographs. HBB did not inactivate the infectivity of poliovirus type 2.

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Section: (From the Rockefeller Institute And The Merck Sharp And Dohsupporting

confidence: 83%

Section: (From the Rockefeller Institute And The Merck Sharp And Dohmentioning

confidence: 99%

Section: (From the Rockefeller Institute And The Merck Sharp And Dohmentioning

confidence: 99%

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Relationship Between Structure of Benzimidazole Derivatives and Selective Virus Inhibitory Activity

Tamm

Bablanian

Nemes

et al. 1961

The Journal of Experimental Medicine

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“…2C). This result is in agreement with an earlier observation that the cytotoxic effect of DRB is nonprogressive at moderate concentrations of the drug (27). Just as removal of DRB immediately reversed the inhibition of RNA synthesis (Fig.…”

Section: Methodssupporting

confidence: 82%

An evaluation of messenger RNA competition in the shutoff of human interferon production.

Sehgal¹,

Tamm²

1976

Proc. Natl. Acad. Sci. U.S.A.

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Contributed by Igor Tamm, February 6,1976 .--D-ribofuranosylbenzimidazole/actinomy ABSTRACIThe process that shuts off poly(I).poly(C-induced interferon production in a strain of diploid human fibroblasts (FS-4) involves the synthesis of new RNA, presumably nuclear heterogeneous RNA. When cultures in the shutoff phase of interferon production are treated with actinomycin D (5 Ag/ml) or 5,6-dichloro-1-4-D-ribofuranosylbenzimidazole (DRB, 40 ;&M), the rate of interferon production continues to decline for a further 3-4 hr, but then tends to level off. The treated cultures maintain interferon production at a reduced level for at least 10 hr. The residual rate of interferon production is higher in cultures which received actinomycin D or DRB early in the shutoff phase as compared to the rate in cultures treated late. Actinomycin D and DRB reduced the overall rate of cellular RNA synthesis by >98% and 60%, respectively. These kinetic data are incompatible with the possibility that the shutoff of interferon production is due to simple competition by newly synthesized mRNA. On the other hand, these data are consistent with the post-transcriptional repressor hypothesis and suggest that the putative repressor system that shuts off interferon production has a life-time of 3-4 hr at 370 and that its effect on the synthesis of interferon is largely irreversible.Inhibitors of RNA and protein synthesis can enhance poly-(inosinic acid)-poly(cytidylic acid) [poly(I)-poly(C)]-induced interferon production (1). Appropriate use of inhibitors of RNA and protein synthesis leads to a 10-to 100-fold increase in interferon yield from poly(I)-poly(C)-induced human or rabbit cells (2-6). The rate of interferon production in human or rabbit cells treated with poly(I)-poly(C) peaks approximately 3 hr after induction and is shut off by 6-8 hr (4, 6, 7). The increase in interferon yield obtained by treating induced cultures with inhibitors of RNA or protein synthesis appears to be due to interference with the normal rapid shutoff (1-6, 8, 9).An enhancement of the amount of a protein or enzyme activity which follows treatment of a cell system with inhibitors of RNA or protein synthesis has now been observed in a large number of different systems (10, 11). Several different hypotheses have been put forward to explain this phenomenon, which is often termed "superinduction" (10-14). Extension of these hypotheses to interferon superinduction has led to the suggestion that the shutoff of interferon production could be due to a post-transcriptional repressor inhibiting translation of interferon mRNA (1)(2)(3)(4)(5)8). Alternative explanations for the shutoff have also been considered, such as intracellular degradation of interferon or inhibition of the translation of interferon messenger RNA (mRNA) through competition by newly synthesized cellular mRNA (1, 7-9).We have recently obtained new evidence that the process which shuts off poly(I)-poly(C)-induced interferon production in a strain of diploid human fibroblasts (FS-4) is a post-transcrip...

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“…The first was the discovery that certain N-glycosides of benzimidazole, particularly 5,6-dichloro-(DRB) and 4,5,6-trichloro-l-{3-D-ribofuranosylbenzimidazole ( (323) (TRB), are potent inhibitors of virus multiplication [712][713][714][715][716][717][718][719][720][721]. These compounds have been shown also to inhibit the growth of vitamin Bt2 -dependent micro-organisms, such as E. coli [722,723].…”

Section: Benzimidazolesmentioning

confidence: 99%