Novel 2-phenyl-5-[(E)-2-(thiophen-2-yl)ethenyl]-1,3,4-oxadiazole and 3-phenyl-5-[(E)-2-(thiophen-2-yl)ethenyl]-1,2,4-oxadiazole derivatives as dengue virus inhibitors targeting NS5 polymerase

Eur J Med Chem. 2016 Feb 15:109:146-56. doi: 10.1016/j.ejmech.2015.12.046. Epub 2015 Dec 29.

Abstract

Using a functional high-throughput screening (HTS) and subsequent SAR studies, we have discovered a novel series of non-nucleoside dengue viral polymerase inhibitors. We report the elaboration of SAR around hit compound 1 as well as the synthesis and antiviral evaluation of 3-phenyl-5-[(E)-2-(thiophen-2-yl)ethenyl]-1,2,4-oxadiazole and 5-phenyl-2-[2-(2-thienyl)ethenyl]-1,3,4-oxadiazole analogues derived from a rapid and easily accessible chemical pathway. A large number of compounds prepared by this method were shown to possess in vitro activity against the polymerase of dengue virus. The most potent inhibitors were tested against Dengue virus clinical isolates on infected cells model and exhibit submicromolar activity on the four dengue virus serotypes.

Keywords: 2-phenyl-5-[(E)-2-(thiophen-2-yl)ethenyl]-1,3,4-oxadiazole; 3-phenyl-5-[(E)-2-(thiophen-2-yl)ethenyl]-1,2,4-oxadiazole; Antiviral activity; Dengue virus; NS5 RdRp inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Cell Line
  • Dengue / drug therapy*
  • Dengue / virology
  • Dengue Virus / drug effects*
  • Dengue Virus / enzymology
  • Humans
  • Oxadiazoles / chemistry
  • Oxadiazoles / pharmacology*
  • RNA-Dependent RNA Polymerase / antagonists & inhibitors*
  • RNA-Dependent RNA Polymerase / metabolism
  • Thiophenes / chemistry
  • Thiophenes / pharmacology
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / metabolism

Substances

  • Antiviral Agents
  • Oxadiazoles
  • Thiophenes
  • Viral Nonstructural Proteins
  • 1,3,4-oxadiazole
  • RNA-Dependent RNA Polymerase