(S)-N-(2,5-Dimethylphenyl)-1-(quinoline-8-ylsulfonyl)pyrrolidine-2-carboxamide as a small molecule inhibitor probe for the study of respiratory syncytial virus infection

J Med Chem. 2012 Oct 25;55(20):8582-7. doi: 10.1021/jm300612z. Epub 2012 Oct 16.

Abstract

A high-throughput, cell-based screen was used to identify chemotypes as inhibitors for human respiratory syncytial virus (hRSV). Optimization of a sulfonylpyrrolidine scaffold resulted in compound 5o that inhibited a virus-induced cytopathic effect in the entry stage of infection (EC₅₀ = 2.3 ± 0.8 μM) with marginal cytotoxicity (CC₅₀ = 30.9 ± 1.1 μM) and reduced viral titer by 100-fold. Compared to ribavirin, sulfonylpyrrolidine 5o demonstrated an improved in vitro potency and selectivity index.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cytopathogenic Effect, Viral / drug effects
  • High-Throughput Screening Assays
  • Humans
  • Pyrrolidines / chemical synthesis*
  • Pyrrolidines / chemistry
  • Pyrrolidines / pharmacology
  • Quinolines / chemical synthesis*
  • Quinolines / chemistry
  • Quinolines / pharmacology
  • Respiratory Syncytial Viruses / drug effects*
  • Respiratory Syncytial Viruses / physiology
  • Ribavirin / pharmacology
  • Stereoisomerism
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology
  • Sulfones / chemical synthesis*
  • Sulfones / chemistry
  • Sulfones / pharmacology
  • Viral Load / drug effects
  • Virus Internalization / drug effects
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • N-(2,5-dimethylphenyl)-1-(quinolin-8-ylsulfonyl)pyrrolidine-2-carboxamide
  • Pyrrolidines
  • Quinolines
  • Sulfonamides
  • Sulfones
  • Ribavirin