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

Dinesh Manvar; İlkay Küçükgüzel; Gizem Erensoy; Esra Tatar; Gökhan Deryabaşoğulları; Haarika Reddy; Tanaji T Talele; Ozge Cevik; Neerja Kaushik-Basu

doi:10.1016/j.bbrc.2015.12.042

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.

Authors

Dinesh Manvar¹, İlkay Küçükgüzel², Gizem Erensoy², Esra Tatar², Gökhan Deryabaşoğulları², Haarika Reddy¹, Tanaji T Talele³, Ozge Cevik¹, Neerja Kaushik-Basu⁴

Affiliations

¹ Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers, The State University of New Jersey, New Jersey Medical School, 185 South Orange Avenue, NJ 07103, USA.
² Marmara University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Haydarpaşa, 34668, İstanbul, Turkey.
³ St. John's University, Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Queens, NY 11439, USA.
⁴ Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers, The State University of New Jersey, New Jersey Medical School, 185 South Orange Avenue, NJ 07103, USA. Electronic address: kaushikbasu.neerja@gmail.com.

PMID: 26697747
DOI: 10.1016/j.bbrc.2015.12.042

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.

Published by Elsevier Inc.

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