Perspectives for the Treatment of Infections with Flaviviridae

Leyssen, Pieter; Clercq, Erik De; Neyts, Johan

doi:10.1128/cmr.13.1.67-82.2000

Cited by 139 publications

(95 citation statements)

References 239 publications

(179 reference statements)

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“…The virus RNA genome encodes a polyprotein, which is posttranslationally processed by host and virus proteases into 10 mature proteins, of which 4 are structural proteins (C, E1, E2, and p7) and 6 nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) [2]. HCV is a worldwide infectious pathogen that causes chronic liver diseases, including hepatic fibrosis, hepatic cirrhosis and hepatocellular carcinoma (HCC) [3]. Until recently, HCV-infected patients were treated with a combination of pegylated interferon-a (IFN-a) and the nucleoside analog ribavirin.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of novel diflunisal hydrazide–hydrazones as anti-hepatitis C virus agents and hepatocellular carcinoma inhibitors

Şenkardeş

Kaushik‐Basu

Durmaz

et al. 2016

European Journal of Medicinal Chemistry

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a b s t r a c tHepatitis C virus (HCV) infection is a main cause of chronic liver disease, leading to liver cirrhosis and hepatocellular carcinoma (HCC). The objective of our research was to develop effective agents against viral replication. We have previously identified the hydrazideehydrazone scaffold as a promising hepatitis C virus (HCV) and hepatocelluler inhibitor. Herein we describe the design a number of 2 0 ,4 0 -difluoro-4-hydroxy-N'-(arylmethylidene) biphenyl-3-carbohydrazide (3a-t) as anti-HCV and anticancer agents. Results from evaluation of anti-HCV activity indicated that most of the synthesized hydrazone derivatives inhibited viral replication in the Huh7/Rep-Feo1b and Huh 7.5-FGR-JCI-Rluc2A reporter systems. Antiproliferative activities of increasing concentrations of 2 0 ,4 0 -difluoro-4-hydroxy-N'-(2-pyridyl methylidene)biphenyl-3-carbohydrazide 3b and diflunisal (2.5e40 mM) were assessed in liver cancer cell lines (Huh7, HepG2, Hep3B, Mahlavu, FOCUS and SNU-475) with sulforhodamine B assay for 72 h. Compound 3b with 2-pyridinyl group in the hydrazone part exhibited promising cytotoxic activity against all cell lines with IC 50 values of 10, 10.34 16.21 4.74, 9.29 and 8.33 mM for Huh7, HepG2, Hep3B, Mahlavu, FOCUS and SNU-475 cells, respectively, and produced dramatic cell cycle arrest at SubG1/G0 phase as an indicator of apoptotic cell death induction.

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Section: Introductionmentioning

confidence: 99%

Synthesis of novel diflunisal hydrazide–hydrazones as anti-hepatitis C virus agents and hepatocellular carcinoma inhibitors

Şenkardeş

Kaushik‐Basu

Durmaz

et al. 2016

European Journal of Medicinal Chemistry

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“…Ribavirin is a synthetic nucleoside which is structurally similar to guanosine [14,15]. Ribavirin enters into the eukaryotic cells rapidly and, after it undergoes intracellular phosphorylation, shows virustatic activity against a broad spectrum of DNA and RNA viruses [14,15].…”

Section: Pharmacological Characteristics Of Ribavirinmentioning

confidence: 99%

Basic aspects of the treatment for hepatitis C: mechanisms of action of interferon alpha and ribavirin and the bases of individualization

2007

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“…Chronic hepatitis C, whether symptomatic or asymptomatic, can lead to cirrhosis and endstage liver disease in 20-30% of patients, and among these, 1-4% may develop hepatocellular carcinoma. [3][4][5][6] Because of the spectrum of liver diseases, since its identification in 1989, HCV infection has been viewed as a serious threat to human health worldwide. The currently approved therapeutic protocol includes a combination of pegylated interferon and ribavirin.…”

Section: Introductionmentioning

confidence: 99%

Simple but Highly Effective Three-Dimensional Chemical-Feature-Based Pharmacophore Model for Diketo Acid Derivatives as Hepatitis C Virus RNA-Dependent RNA Polymerase Inhibitors

et al. 2005

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A molecular modeling strategy using aryl diketo acid (ADK) derivatives recently reported in the literature as hepatitis C virus (HCV) polymerase inhibitors was designed. A 3D chemicalfeature-based pharmacophore model was developed using Catalyst software, which produced 10 pharmacophore hypotheses. The top-ranked one (Hypo 1), characterized by a high correlation coefficient (r ) 0.965), consisted of two hydrogen bond acceptors, one negative ionizable moiety, and two hydrophobic aromatics. This model was used to predict the anti-RNA-dependent RNA polymerase (anti-RdRp) activity of 6-(1-arylmethylpyrrol-2-yl)-1,4-dioxo-5-hexenoic acids and other ADK derivatives previously synthesized in our laboratories as HIV-1 integrase inhibitors. Furthermore, the experimental IC 50 values of 9 compounds, tested in vitro against recombinant HCV polymerase, were compared with the corresponding values predicted using Hypo1. A good agreement between experimental and simulated data was obtained. The results demonstrate that the hypothesis derived in this study can be considered to be a useful tool in designing new leads based on ADK scaffolds as HCV RdRp inhibitors.

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Perspectives for the Treatment of Infections with Flaviviridae

Cited by 139 publications

References 239 publications

Synthesis of novel diflunisal hydrazide–hydrazones as anti-hepatitis C virus agents and hepatocellular carcinoma inhibitors

Synthesis of novel diflunisal hydrazide–hydrazones as anti-hepatitis C virus agents and hepatocellular carcinoma inhibitors

Basic aspects of the treatment for hepatitis C: mechanisms of action of interferon alpha and ribavirin and the bases of individualization

Simple but Highly Effective Three-Dimensional Chemical-Feature-Based Pharmacophore Model for Diketo Acid Derivatives as Hepatitis C Virus RNA-Dependent RNA Polymerase Inhibitors

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