Discovery of conjugated thiazolidinone-thiadiazole scaffold as anti-dengue virus polymerase inhibitors.
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.
['Manvar|Dinesh|D|', 'Küçükgüzel|İlkay|İ|', 'Erensoy|Gizem|G|', 'Tatar|Esra|E|', 'Deryabaşoğulları|Gökhan|G|', 'Reddy|Haarika|H|', 'Talele|Tanaji T|TT|', 'Cevik|Ozge|O|', 'Kaushik-Basu|Neerja|N|']
D001665:Binding Sites D012321:DNA-Directed RNA Polymerases D004338:Drug Combinations D055808:Drug Discovery D008956:Models, Chemical D062105:Molecular Docking Simulation D011485:Protein Binding D011487:Protein Conformation D013830:Thiadiazoles D045162:Thiazolidinediones D017361:Viral Nonstructural Proteins
Dengue virus 1,3,4-Thiadiazoles NS5 polymerase 4-Thiazolidinones Fluorescence quenching RNA dependent RNA polymerase