Discovery of Conjugated Thiazolidinone-Thiadiazole Scaffold as Anti-Dengue Virus Polymerase Inhibitors

Biochem Biophys Res Commun. 2016 Jan 15;469(3):743-7. doi: 10.1016/j.bbrc.2015.12.042. Epub 2015 Dec 15.

Abstract

Dengue virus (DENV) infection is a significant health threat to the global population with no therapeutic option. DENV NS5 RNA-dependent RNA polymerase (RdRp) is the key replicating protein of the virus and thus an attractive target for drug development. Herein, we report on the synthesis and biological evaluation of a series of hybrid thiazolidinone-thiadiazole derivatives as a new class of DENV-2 NS5 RdRp inhibitors. This yielded compounds 12 and 21 with IC50 values of 2.3 μM and 2.1 μM, respectively, as promising leads. Limited SAR analysis indicated 3-fluorobenzylidene as the optimal substituent at C5-position of the thiazolidinone core, whereas both 2-chlorophenyl and 3-fluorophenyl substituents were equally effective at C5-position of the 1,3,4-thiadiazole core. Biophysical characterization and molecular docking studies conferred the binding site of this scaffold on DENV NS5 polymerase. Binding mode of compound 21 in Thumb pocket-II of DENV-2 NS5 polymerase will form the basis for future structure-activity relationship optimization.

Keywords: 1,3,4-Thiadiazoles; 4-Thiazolidinones; Dengue virus; Fluorescence quenching; NS5 polymerase; RNA dependent RNA polymerase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • DNA-Directed RNA Polymerases / antagonists & inhibitors*
  • DNA-Directed RNA Polymerases / ultrastructure*
  • Drug Combinations
  • Drug Discovery
  • Models, Chemical
  • Molecular Docking Simulation
  • Protein Binding
  • Protein Conformation
  • Thiadiazoles / administration & dosage
  • Thiadiazoles / chemistry*
  • Thiazolidinediones / administration & dosage
  • Thiazolidinediones / chemistry*
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / ultrastructure*

Substances

  • Drug Combinations
  • NS5 protein, dengue virus
  • Thiadiazoles
  • Thiazolidinediones
  • Viral Nonstructural Proteins
  • DNA-Directed RNA Polymerases