<i>In vitro</i> anti-HCV activity of Artemisinin and its selected analogues on the replication of infectious HCVcc as measured by means of qRT-PCR (n = 4).

<p>a) ART; b) TVN4; c) AJ-002 and d) AJ-004. Bars indicate the HCV RNA level as compared to control (%) and lines represent the cell growth as compared to untreated controls (%).</p

Structural formulae of Artemisinin and synthetic derivatives belonging to the second category TVN.

<p>Structural formulae of Artemisinin and synthetic derivatives belonging to the second category TVN.</p

Structural formulae of Artemisinin and synthetic derivatives belonging to the first category AJ.

<p>Structural formulae of Artemisinin and synthetic derivatives belonging to the first category AJ.</p

Effect of ART and derivatives on Huh 5-2 HCV replicon replication.

<p>∶ 50% effective concentration, CC50∶ 50% cytostatic concentration. Data obtained from the measurement of the firefly luciferase activity, and are mean values ± SD for four independent experiments (expressed in µM). EC50</p><p>µM, Hemin inhibits HCV replicon replication by 30%. Values between brackets indicate fold-change. At 5 </p

Structure-Based Discovery of Pyrazolobenzothiazine Derivatives As Inhibitors of Hepatitis C Virus Replication

The NS5B RNA-dependent RNA polymerase is an attractive target for the development of novel and selective inhibitors of hepatitis C virus replication. To identify novel structural hits as anti-HCV agents, we performed structure-based virtual screening of our in-house library followed by rational drug design, organic synthesis, and biological testing. These studies led to the identification of pyrazolobenzothiazine scaffold as a suitable template for obtaining novel anti-HCV agents targeting the NS5B polymerase. The best compound of this series was the <i>meta</i>-fluoro-<i>N</i>-1-phenyl pyrazolobenzothiazine derivative <b>4a</b>, which exhibited an EC₅₀ = 3.6 μM, EC₉₀ = 25.6 μM, and CC₅₀ > 180 μM in the Huh 9–13 replicon system, thus providing a good starting point for further hit evolution