Synthesis of 4'-Substituted-2'-Deoxy-2'-α-Fluoro Nucleoside Analogs as Potential Antiviral Agents

Molecules. 2020 Mar 11;25(6):1258. doi: 10.3390/molecules25061258.

Abstract

Nucleoside analogs are widely used for the treatment of viral diseases (Hepatitis B/C, herpes and human immunodeficiency virus, HIV) and various malignancies. ALS-8176, a prodrug of the 4'-chloromethyl-2'-deoxy-2'-fluoro nucleoside ALS-8112, was evaluated in hospitalized infants for the treatment of respiratory syncytial virus (RSV), but was abandoned for unclear reasons. Based on the structure of ALS-8112, a series of novel 4'-modified-2'-deoxy-2'-fluoro nucleosides were synthesized. Newly prepared compounds were evaluated against RSV, but also against a panel of RNA viruses, including Dengue, West Nile, Chikungunya, and Zika viruses. Unfortunately, none of the compounds showed marked antiviral activity against these viruses.

Keywords: Chikungunya; Dengue; West Nile; Zika; nucleoside; polymerase inhibitors; respiratory syncytial virus; virus.

MeSH terms

  • Animals
  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / pharmacology
  • Cell Line, Tumor
  • Chikungunya virus / drug effects
  • Chikungunya virus / growth & development
  • Cricetulus
  • Dengue Virus / drug effects
  • Dengue Virus / growth & development
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / chemical synthesis
  • Deoxycytidine / pharmacology
  • Deoxyribonucleosides / chemical synthesis*
  • Deoxyribonucleosides / pharmacology
  • Epithelial Cells / drug effects
  • Epithelial Cells / virology
  • Hepatocytes / drug effects
  • Hepatocytes / virology
  • Humans
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / virology
  • Microbial Sensitivity Tests
  • Primary Cell Culture
  • Prodrugs / chemical synthesis*
  • Prodrugs / pharmacology
  • Respiratory Syncytial Virus, Human / drug effects
  • Respiratory Syncytial Virus, Human / growth & development
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / virology
  • Treatment Failure
  • Virus Replication / drug effects
  • West Nile virus / drug effects
  • West Nile virus / growth & development
  • Zika Virus / drug effects
  • Zika Virus / growth & development

Substances

  • Antiviral Agents
  • Deoxyribonucleosides
  • Prodrugs
  • Deoxycytidine
  • 4'-chloromethyl-2'-deoxy-3',5'-di-O-isobutyryl-2'-fluorocytidine