Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1961 Mar 31;113(4):625–656. doi: 10.1084/jem.113.4.625

RELATIONSHIP BETWEEN STRUCTURE OF BENZIMIDAZOLE DERIVATIVES AND SELECTIVE VIRUS INHIBITORY ACTIVITY

INHIBITION OF POLIOVIRUS MULTIPLICATION AND CYTOPATHIC EFFECTS BY 2-(α-HYDROXYBENZYL)-BENZIMIDAZOLE, AND ITS 5-CHLORO DERIVATIVE

Igor Tamm 1, Rostom Bablanian 1, Marjorie M Nemes 1, Clifford H Shunk 1, Franklin M Robinson 1, Karl Folkers 1
PMCID: PMC2137381  PMID: 13775109

Abstract

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.

Full Text

The Full Text of this article is available as a PDF (2.0 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. ALLFREY V. G., MIRSKY A. E., OSAWA S. Protein synthesis in isolated cell nuclei. J Gen Physiol. 1957 Jan 20;40(3):451–490. doi: 10.1085/jgp.40.3.451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Allfrey V. G., Mirsky A. E. SOME ASPECTS OF RIBONUCLEIC ACID SYNTHESIS IN ISOLATED CELL NUCLEI. Proc Natl Acad Sci U S A. 1957 Sep 15;43(9):821–826. doi: 10.1073/pnas.43.9.821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. EAGLE H. The minimum vitamin requirements of the L and HeLa cells in tissue culture, the production of specific vitamin deficiencies, and their cure. J Exp Med. 1955 Nov 1;102(5):595–600. doi: 10.1084/jem.102.5.595. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. EGGERS H. J., TAMM I. Spectrum and characteristics of the virus inhibitory action of 2-(alpha-hydroxybenzyl)-benzimidazole. J Exp Med. 1961 Apr 1;113:657–682. doi: 10.1084/jem.113.4.657. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. HOLLINSHEAD A. C., SMITH P. K. Effects of certain purines and related compounds on virus propagation. J Pharmacol Exp Ther. 1958 May;123(1):54–62. [PubMed] [Google Scholar]
  6. KILBOURNE E. D. Reactivation of non-infective virus in a cortisone-injected host. J Exp Med. 1955 Apr 1;101(4):437–450. doi: 10.1084/jem.101.4.437. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. TAMM I. Enhancement of influenza virus multiplication by 5-methyl-2-D-ribobenzimidazole. Virology. 1956 Aug;2(4):517–531. doi: 10.1016/0042-6822(56)90008-3. [DOI] [PubMed] [Google Scholar]
  8. TAMM I., FOLKERS K., SHUNK C. H., HEYL D., HORSFALL F. L., Jr Inhibition of influenza virus multiplication by alkyl derivatives of benzimidazole. III. Relationship between inhibitory activity and chemical structure. J Exp Med. 1953 Sep;98(3):245–259. doi: 10.1084/jem.98.3.245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. TAMM I., FOLKERS K., SHUNK C. H., HORSFALL F. L., Jr Inhibition of influenza virus multiplication by N-glycosides of benzimidazoles-N. J Exp Med. 1954 Mar;99(3):227–250. doi: 10.1084/jem.99.3.227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. TAMM I., FOLKERS K., SHUNK C. H. High inhibitory activity of certain halogenated ribofuranosylbenzimidazoles on influenza B virus multiplication. J Bacteriol. 1956 Jul;72(1):54–58. doi: 10.1128/jb.72.1.54-58.1956. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. TAMM I. Inhibition of influenza and mumps virus multiplication by 4,5,6- (or 5,6,7-) trichloro-1-beta-D-ribofuranosyl-benzimidazole. Science. 1954 Nov 19;120(3125):847–848. doi: 10.1126/science.120.3125.847. [DOI] [PubMed] [Google Scholar]
  12. TAMM I., NEMES M. M. Glycosides of chlorobenzimidazoles as inhibitors of poliovirus multiplication. Virology. 1957 Dec;4(3):483–498. doi: 10.1016/0042-6822(57)90081-8. [DOI] [PubMed] [Google Scholar]
  13. TAMM I., NEMES M. M., OSTERHOUT S. On the role of ribonucleic acid in animal virus synthesis. I. Studies with 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole. J Exp Med. 1960 Mar 1;111:339–349. doi: 10.1084/jem.111.3.339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. TAMM I., OVERMAN J. R. Relationship between structure of benzimidazole derivatives and inhibitory activity on vaccinia virus multiplication. Virology. 1957 Feb;3(1):185–196. doi: 10.1016/0042-6822(57)90032-6. [DOI] [PubMed] [Google Scholar]
  15. TAMM I., TYRRELL D. A. Influenza virus multiplication in the chorioallantoic membrane in vitro: kinetic aspects of inhibition by 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole. J Exp Med. 1954 Dec 1;100(6):541–562. doi: 10.1084/jem.100.6.541. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. TYRRELL D. A., TAMM I. Prevention of virus interference by 2,5-dimethylbenzimidazole. J Immunol. 1955 Jul;75(1):43–49. [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES