Optimization of potent and selective quinazolinediones: inhibitors of respiratory syncytial virus that block RNA-dependent RNA-polymerase complex activity

J Med Chem. 2014 Dec 26;57(24):10314-28. doi: 10.1021/jm500902x. Epub 2014 Dec 4.

Abstract

A quinazolinedione-derived screening hit 2 was discovered with cellular antiviral activity against respiratory syncytial virus (CPE EC50 = 2.1 μM), moderate efficacy in reducing viral progeny (4.2 log at 10 μM), and marginal cytotoxic liability (selectivity index, SI ∼ 24). Scaffold optimization delivered analogs with improved potency and selectivity profiles. Most notable were compounds 15 and 19 (EC50 = 300-500 nM, CC50 > 50 μM, SI > 100), which significantly reduced viral titer (>400,000-fold), and several analogs were shown to block the activity of the RNA-dependent RNA-polymerase complex of RSV.

Publication types

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

MeSH terms

  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / pharmacology*
  • Benzamides / chemical synthesis
  • Benzamides / pharmacology*
  • Cell Proliferation / drug effects*
  • Drug Design
  • Hep G2 Cells
  • Humans
  • Inhibitory Concentration 50
  • Models, Molecular
  • Molecular Structure
  • Quinazolinones / chemical synthesis
  • Quinazolinones / chemistry
  • Quinazolinones / pharmacology*
  • RNA-Dependent RNA Polymerase / antagonists & inhibitors*
  • RNA-Dependent RNA Polymerase / metabolism
  • Respiratory Syncytial Virus Infections / drug therapy*
  • Respiratory Syncytial Virus Infections / virology
  • Respiratory Syncytial Viruses / drug effects*
  • Structure-Activity Relationship
  • Virus Replication / drug effects*

Substances

  • Antiviral Agents
  • Benzamides
  • N-(3-methoxypropyl)-4-((1-(4-nitrobenzyl)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)methyl)benzamide
  • Quinazolinones
  • RNA-Dependent RNA Polymerase