Synthesis and antiviral evaluation of trisubstituted indole N-nucleosides as analogues of 2,5,6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole (TCRB)

J Med Chem. 2000 Jun 15;43(12):2449-56. doi: 10.1021/jm990320x.

Abstract

2,5,6-Trichloro-1-(beta-D-ribofuranosyl)benzimidazole (TCRB) and 2-bromo-5,6-dichloro-1-(beta-D-ribofuranosyl)benzimidazole (BDCRB) are nucleosides that exhibit strong and selective activity against human cytomegalovirus (HCMV). Selected polyhalogenated indole nucleosides have now been synthesized as 3-deaza analogues of the benzimidazole nucleosides using the sodium salt glycosylation method. 2-Benzylthio-1-¿2-deoxy-3, 5-bis-O-(4-methylbenzoyl)-beta-D-erythro-pentofuranosyl-5, 6-dichloroindole (8) was prepared stereoselectively via the coupling of a 2-deoxyribofuranosyl alpha-chloride derivative with the sodium salt of 2-benzylthio-5,6-dichloroindole (5). Compound 8 was then elaborated into the targeted 2-benzylthio-1-(beta-D-ribofuranosyl)-5, 6-dichloroindole (18) in five steps. 2,5, 6-Trichloro-(1-beta-D-ribofuranosyl)indole (19) was prepared using the same synthetic route with 2,5,6-trichloroindole (6) as the starting material. We were subsequently able to prepare 19 in three steps using a modification of the sodium salt glycosylation method. 2-Bromo-5,6-dichloro-1-(beta-D-ribofuranosyl)indole (25) was also prepared using the same procedures. Target compounds were tested for activity against HCMV, herpes simplex virus type 1 (HSV-1), and human herpes virus six (HHV-6) and for cytotoxicity. All of the compounds were less active against HCMV than TCRB and weakly active or inactive against HSV-1 and HHV-6.

Publication types

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

MeSH terms

  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • Benzimidazoles / chemistry*
  • Cell Division / drug effects
  • Cell Line
  • Cytomegalovirus / drug effects
  • Enzyme-Linked Immunosorbent Assay
  • Herpesvirus 1, Human / drug effects
  • Herpesvirus 6, Human / drug effects
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / pharmacology
  • Ribonucleosides / chemical synthesis*
  • Ribonucleosides / chemistry*
  • Ribonucleosides / pharmacology
  • Structure-Activity Relationship
  • Viral Plaque Assay

Substances

  • 2,5,6-trichloro-1-(ribofuranosyl)benzimidazole
  • Antiviral Agents
  • Benzimidazoles
  • Indoles
  • Ribonucleosides