title: Discovery of conjugated thiazolidinone-thiadiazole scaffold as anti-dengue virus polymerase inhibitors.
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.
authors.affiliation: 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.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Manvar
authors.affiliation: Marmara University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Haydarpaşa, 34668, İstanbul, Turkey.
authors.forename: İlkay
authors.initials: İ
authors.lastname: Küçükgüzel
authors.affiliation: Marmara University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Haydarpaşa, 34668, İstanbul, Turkey.
authors.forename: Gizem
authors.initials: G
authors.lastname: Erensoy
authors.affiliation: Marmara University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Haydarpaşa, 34668, İstanbul, Turkey.
authors.forename: Esra
authors.initials: E
authors.lastname: Tatar
authors.affiliation: Marmara University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Haydarpaşa, 34668, İstanbul, Turkey.
authors.forename: Gökhan
authors.initials: G
authors.lastname: Deryabaşoğulları
authors.affiliation: 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.
authors.forename: Haarika
authors.initials: H
authors.lastname: Reddy
authors.affiliation: St. John's University, Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Queens, NY 11439, USA.
authors.forename: Tanaji T
authors.initials: TT
authors.lastname: Talele
authors.affiliation: 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.
authors.forename: Ozge
authors.initials: O
authors.lastname: Cevik
authors.affiliation: 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.
authors.forename: Neerja
authors.initials: N
authors.lastname: Kaushik-Basu
mesh_terms: D001665:Binding Sites; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors* / Q000648:ultrastructure*; D004338:Drug Combinations; D055808:Drug Discovery; D008956:Models, Chemical; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011487:Protein Conformation; D013830:Thiadiazoles / Q000008:administration & dosage / Q000737:chemistry*; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000737:chemistry*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000648:ultrastructure*
chemical_list: D004338:Drug Combinations; C582223:NS5 protein, dengue virus; D013830:Thiadiazoles; D045162:Thiazolidinediones; D017361:Viral Nonstructural Proteins; D012321:DNA-Directed RNA Polymerases
keywords: 1,3,4-Thiadiazoles; 4-Thiazolidinones; Dengue virus; Fluorescence quenching; NS5 polymerase; RNA dependent RNA polymerase