Discovery and optimization of 2,4-diaminoquinazoline derivatives as a new class of potent dengue virus inhibitors

J Med Chem. 2012 Apr 12;55(7):3135-43. doi: 10.1021/jm2015952. Epub 2012 Mar 26.

Abstract

The results of a high-throughput screening assay using the DENV-2 replicon showed that the 2,4-diaminoquinazoline derivative 4a has a high dengue virus inhibitory activity (EC(50) = 0.15 μM). A series of 2,4-diaminoquinazoline derivatives based on 4a as a lead compound were synthesized and subjected to structure-antidengue activity relationship studies. Among the series of 2,4-diaminoquinazoline derivative probed, 4o was observed to display both the highest antiviral potency (EC(50) = 2.8 nM, SI > 1000) and an excellent pharmacokinetic profile.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / pharmacokinetics
  • Antiviral Agents / pharmacology
  • Cell Line
  • Dengue Virus / drug effects*
  • Dengue Virus / genetics
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
  • High-Throughput Screening Assays
  • Humans
  • Quinazolines / chemical synthesis*
  • Quinazolines / pharmacokinetics
  • Quinazolines / pharmacology
  • Rats
  • Replicon / drug effects
  • Structure-Activity Relationship

Substances

  • 5-tert-butoxyquinazoline-2,4-diamine
  • Antiviral Agents
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • Quinazolines