Dataset Information

The versatile nature of the 6-aminoquinolone scaffold: identification of submicromolar hepatitis C virus NS5B inhibitors.

ABSTRACT: 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.

SUBMITTER: Manfroni G

PROVIDER: S-EPMC3954902 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The versatile nature of the 6-aminoquinolone scaffold: identification of submicromolar hepatitis C virus NS5B inhibitors.

Manfroni Giuseppe G Cannalire Rolando R Barreca Maria Letizia ML Kaushik-Basu Neerja N Leyssen Pieter P Winquist Johan J Iraci Nunzio N Manvar Dinesh D Paeshuyse Jan J Guhamazumder Rupa R Basu Amartya A Sabatini Stefano S Tabarrini Oriana O Danielson U Helena UH Neyts Johan J Cecchetti Violetta V

Journal of medicinal chemistry 20131106 5

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 ...[more]

PMID: 24131104

Similar Datasets

Project description:IntroductionTreatment of HCV infection with peginterferon and ribavirin results in a low sustained virologic response rate, but has a number of undesirable adverse effects. Direct-acting antivirals (DAAs) offer a high efficacy, low risk, and a short treatment time. However, the existence of resistance-associated mutations, particularly in the NS5B polymerase, can attenuate the efficacy of DAAs. The objective of this study was to identify amino acid changes in the NS5B gene linked to DAA resistance in treatment-naive Vietnamese chronic hepatitis C patients.MethodsBlood samples and treatment data were collected from 100 HCV-infected patients hospitalized at the National Hospital for Tropical Diseases between January and December 2020; the plasma was then isolated and stored at -80°C for molecular analysis. The NS5B gene fragments of 100 samples were amplified with specified primers and the nucleotide sequences were obtained using the Sanger sequencing system. The nucleotide sequences were then analyzed and compared to identify substitutions in the NS5B region.ResultsA total of 100 HCV isolates from patients were classified into three genotypes, including genotypes 1, 3, and 6. The NS5B sequence analysis revealed many amino acid mutations in all genotypes, although these mutations were not strongly associated with resistance to DAAs like S282T. Analytical data on ribavirin-resistance mutations revealed that Q309R was predominantly found in genotype 1a, D310N was mostly found in genotype 1b, and N244I, T329I, A333E were not observed. The following mutations were shown to be related with DAAs resistance: E237G, S282R, L320F, V321A, and V321I. Furthermore, NS5B-resistance mutations were not associated with clinical characteristics, long-term virological response, or improvements in clinical parameters (liver enzymes or liver fibrosis index).ConclusionAlthough NS5B mutations were found in treatment-naive Vietnamese patients, changes in the NS5B gene did not appear to be highly correlated with HCV ribavirin and DAA antiviral resistance.

Dataset Information

The versatile nature of the 6-aminoquinolone scaffold: identification of submicromolar hepatitis C virus NS5B inhibitors.

Publications

The versatile nature of the 6-aminoquinolone scaffold: identification of submicromolar hepatitis C virus NS5B inhibitors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets