Publication: Discovery of conjugated thiazolidinone-thiadiazole scaffold as anti-dengue virus polymerase inhibitors
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Date
2016
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ACADEMIC PRESS INC ELSEVIER SCIENCE
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.
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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