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Discovery of conjugated thiazolidinone-thiadiazole scaffold as anti-dengue virus polymerase inhibitors.
Manvar, Dinesh; Küçükgüzel, Ilkay; Erensoy, Gizem; Tatar, Esra; Deryabasogullari, Gökhan; Reddy, Haarika; Talele, Tanaji T; Cevik, Ozge; Kaushik-Basu, Neerja.
Affiliation
  • Manvar D; 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.
  • Küçükgüzel I; Marmara University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Haydarpasa, 34668, Istanbul, Turkey.
  • Erensoy G; Marmara University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Haydarpasa, 34668, Istanbul, Turkey.
  • Tatar E; Marmara University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Haydarpasa, 34668, Istanbul, Turkey.
  • Deryabasogullari G; Marmara University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Haydarpasa, 34668, Istanbul, Turkey.
  • Reddy H; 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.
  • Talele TT; St. John's University, Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Queens, NY 11439, USA.
  • Cevik O; 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.
  • Kaushik-Basu N; 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.
Biochem Biophys Res Commun ; 469(3): 743-7, 2016 Jan 15.
Article in En | MEDLINE | ID: mdl-26697747
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Thiadiazoles / DNA-Directed RNA Polymerases / Viral Nonstructural Proteins / Thiazolidinediones Language: En Journal: Biochem Biophys Res Commun Year: 2016 Document type: Article Affiliation country: United States Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Thiadiazoles / DNA-Directed RNA Polymerases / Viral Nonstructural Proteins / Thiazolidinediones Language: En Journal: Biochem Biophys Res Commun Year: 2016 Document type: Article Affiliation country: United States Country of publication: United States