Synthesis and antiviral activity of certain 5'-modified analogs of 2,5,6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole

J Med Chem. 1997 Feb 28;40(5):785-93. doi: 10.1021/jm9604888.

Abstract

A series of 5'-modified 2,5,6-trichlorobenzimidazole ribonucleosides has been synthesized and tested for activity against two human herpesviruses and for cytotoxicity. The 5'-methoxy, 5'-ethoxy, and 5'-butoxy analogs of 2,5,6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole (TCRB) were prepared by coupling the appropriate 5-O-alkyl-1,2,3-tri-O-acetyl-beta-D-ribose derivatives with 2,5,6-trichlorobenzimidazole followed by removal of the protecting groups. The 5'-deoxy-5'-fluoro, -5'-chloro, -5'-bromo, -5'-iodo, -5'-azido, and -5'-thiomethyl derivatives were synthesized in a similar fashion. All of these 5'-modified derivatives had significant activity against HCMV in plaque and yield reduction assays (IC50's = 0.5-14.2 microM) but had little activity (IC50's > 100 microM) against HSV-1. This pattern in similar to the antiviral activity profile observed for TCRB. The 5'-halogenated derivatives were more active than the other 5'-modified derivatives with antiviral activity well separated from cytotoxicity. In general, cytotoxicity of all the 5'-modified derivatives was greater in human foreskin fibroblasts (HFF cells) than in L1210 or KB tumor cells. These results indicate that the viral target tolerates significant modifications of TCRB at the 5'-position without adversely affecting activity against HCMV, whereas the 5'-modifications increased cytotoxicity in human diploid cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Benzimidazoles / chemical synthesis*
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology*
  • Cell Division / drug effects
  • Cells, Cultured
  • Cytomegalovirus / drug effects
  • Humans
  • Magnetic Resonance Spectroscopy
  • Mice
  • Molecular Structure
  • Ribonucleosides / chemical synthesis*
  • Ribonucleosides / chemistry
  • Ribonucleosides / pharmacology*
  • Simplexvirus / drug effects
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Antiviral Agents
  • Benzimidazoles
  • Ribonucleosides