Discovery of conjugated thiazolidinone-thiadiazole scaffold as anti-dengue virus polymerase inhibitors

MANVAR D., KÜÇÜKGÜZEL İ., ERENSOY G., TATAR E., DERYABAŞOĞULLARI G., REDDY H., ...More

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol.469, no.3, pp.743-747, 2016 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 469 Issue: 3
  • Publication Date: 2016
  • Doi Number: 10.1016/j.bbrc.2015.12.042
  • Journal Name: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.743-747
  • Keywords: Dengue virus, NS5 polymerase, RNA dependent RNA polymerase, 4-Thiazolidinones, Fluorescence quenching, 1,3,4-Thiadiazoles, RNA-SYNTHESIS, ADENOSINE NUCLEOSIDE, MYCOPHENOLIC-ACID, IN-VITRO, REPLICATION, INFECTION, ENTRY
  • Marmara University Affiliated: Yes

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 mu M and 2.1 mu M, respectively, as promising leads. Limited SAR analysis indicated 3-fluorobenzylidene as the optimal substituent at C5-position of the thiazolidinone core, whereas both 2-chiorophenyl 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. Published by Elsevier Inc.