ABSTRACT
In continuation of our efforts to develop new derivatives as hepatitis C virus (HCV) NS5B inhibitors, we synthesized novel 5-arylidene-4-thiazolidinones. The novel compounds 29-42, together with their synthetic precursors 22-28, were tested for HCV NS5B inhibitory activity; 12 of these compounds displayed IC50 values between 25.3 and 54.1 µM. Compound 33, an arylidene derivative, was found to be the most active compound in this series with an IC50 value of 25.3 µM. Molecular docking studies were performed on the thumb pocket-II of NS5B to postulate the binding mode for these compounds.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Hepacivirus/drug effects , Thiazolidines/chemical synthesis , Thiazolidines/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/metabolism , Binding Sites , Cell Line, Tumor , Computer-Aided Design , Dose-Response Relationship, Drug , Enzyme Inhibitors/metabolism , Hepacivirus/enzymology , High-Throughput Screening Assays , Humans , Microbial Sensitivity Tests , Molecular Docking Simulation , Molecular Structure , Protein Conformation , Structure-Activity Relationship , Thiazolidines/metabolism , Viral Nonstructural Proteins/metabolismABSTRACT
We have previously reported that the 6-aminoquinolone chemotype is a privileged scaffold to obtain antibacterial and antiviral agents. Herein we describe the design, synthesis, and enzymatic and cellular characterization of new 6-aminoquinolone derivatives as potent inhibitors of NS5B polymerase, an attractive and viable therapeutic target to develop safe anti-HCV agents. The 6-amino-7-[4-(2-pyridinyl)-1-piperazinyl]quinolone derivative 8 proved to be the best compound of this series, exhibiting an IC50 value of 0.069 µM against NS5B polymerase and selective antiviral effect (EC50 = 3.03 µM) coupled with the absence of any cytostatic effect (CC50 > 163 µM; SI > 54) in Huh 9-13 cells carrying a HCV genotype 1b, as measured by MTS assay. These results indicate that the 6-aminoquinolone scaffold is worthy of further investigation in the context of NS5B-targeted HCV drug discovery programs.
