New acridone-4-carboxylic acid derivatives as potential inhibitors of Hepatitis C virus infection

A series of N-substituted acridone-4-carboxamides have been synthesized and their anti-HCV and anti-T7 polymerase activity tested. Two compounds were efficient inhibitors of HCV RNA replication in a human hepatoma cell line. A new class of compounds—acridone derivatives—was tested using the direct f...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry Vol. 16; no. 19; pp. 8846 - 8852
Main Authors:	Stankiewicz-Drogon, Anna, Palchykovska, Larisa G., Kostina, Valentina G., Alexeeva, Inna V., Shved, Anatoly D., Boguszewska-Chachulska, Anna M.
Format:	Journal Article
Language:	English
Published:	Amsterdam Elsevier Ltd 01-10-2008 Elsevier
Subjects:	Acridone derivative Acridones - chemical synthesis Acridones - pharmacology Anti-HCV drugs Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Antiviral Agents - chemical synthesis Antiviral Agents - pharmacology Biological and medical sciences Carboxylic Acids - chemical synthesis Carboxylic Acids - pharmacology DNA-Directed RNA Polymerases - antagonists & inhibitors Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - pharmacology Fluorometric assay Fluorometry Hepacivirus - drug effects Hepacivirus - enzymology Hepatitis C virus Inhibitory Concentration 50 Intercalation Medical sciences NS3 helicase Pharmacology. Drug treatments RNA Helicases - antagonists & inhibitors RNA Helicases - metabolism RNA Viruses - drug effects Structure-Activity Relationship Subgenomic HCV replicon Virus Replication - drug effects Acridone derivative Subgenomic HCV replicon NS3 helicase Anti-HCV drugs Hepatitis C virus Intercalation Fluorometric assay Nitrogen heterocycle Pyridine derivatives Structure activity relation Carboxylic acid Antiviral Aromatic compound Inhibition Chemical synthesis Enzyme Transferases Enzyme inhibitor Virus replication cycle Tricyclic compound In vitro Virus Nucleotidyltransferases Position isomer Flaviviridae Hepacivirus
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Summary:	A series of N-substituted acridone-4-carboxamides have been synthesized and their anti-HCV and anti-T7 polymerase activity tested. Two compounds were efficient inhibitors of HCV RNA replication in a human hepatoma cell line. A new class of compounds—acridone derivatives—was tested using the direct fluorometric helicase activity assay to determine the inhibitory properties of the derivatives towards the NS3 helicase of Hepatitis C virus (HCV). The compounds were also tested as putative transcription inhibitors of in vitro transcription based on the DNA-dependent T7 RNA polymerase. Most of the acridone derivatives tested were transcription inhibitors; however, only four of them inhibited the NS3 helicase at low concentrations (IC 50 from 3 μM to 20 μM) and were therefore selected for further studies on the mechanism of inhibition. The acridone derivatives probably act via intercalation into double-stranded nucleic acids but they may also interact directly with viral enzymes. Selected carboxamides were tested in the subgenomic HCV replicon system. Two of the compounds: N-(pyridin-4-yl)-amide and N-(pyridin-2-yl)-amide of acridone-4-carboxylic acid are efficient RNA replication inhibitors with selectivity indexes of 19.4 and 40.5, respectively, proving that the acridone derivatives may be regarded as potential antiviral agents.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0968-0896 1464-3391
DOI:	10.1016/j.bmc.2008.08.074