title: 2-Heteroarylimino-5-arylidene-4-thiazolidinones as a new class of non-nucleoside inhibitors of HCV NS5B polymerase.
abstract: Hepatitis C virus (HCV) NS5B polymerase is an important and attractive target for the development of anti-HCV drugs. Here we report on the design, synthesis and evaluation of twenty-four novel allosteric inhibitors bearing the 4-thiazolidinone scaffold as inhibitors of HCV NS5B polymerase. Eleven compounds tested were found to inhibit HCV NS5B with IC₅₀ values ranging between 19.8 and 64.9 μM. Compound 24 was the most active of this series with an IC₅₀ of 5.6 μM. A number of these derivatives further exhibited strong inhibition against HCV 1b and 2a genotypes in cell based antiviral assays. Molecular docking analysis predicted that the thiazolidinone derivatives bind to the NS5B thumb pocket-II (TP-II). Our results suggest that further optimization of the thiazolidinone scaffold may be possible to yield new derivatives with improved enzyme- and cell-based activity.
authors.affiliation: Marmara University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Haydarpaşa, 34668 İstanbul, Turkey. Electronic address: ikucukguzel@marmara.edu.tr.
authors.forename: Ilkay
authors.initials: I
authors.lastname: Küçükgüzel
authors.forename: Gökhan
authors.initials: G
authors.lastname: Satılmış
authors.forename: K R
authors.initials: KR
authors.lastname: Gurukumar
authors.forename: Amartya
authors.initials: A
authors.lastname: Basu
authors.forename: Esra
authors.initials: E
authors.lastname: Tatar
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Nichols
authors.forename: Tanaji T
authors.initials: TT
authors.lastname: Talele
authors.forename: Neerja
authors.initials: N
authors.lastname: Kaushik-Basu
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D053778:Thiazolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D053778:Thiazolidines; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: AP; Antiviral agents; HCV; HCV NS5B polymerase; Hepatitis C; NI; NNI; PP-I; RNA-dependent RNA polymerase; RdRp; SP; TP; Thiazolidinones; allosteric pocket; hepatitis C virus; non-nucleoside inhibitor; nucleoside inhibitor; palm pocket-I; subpocket; thumb pocket