title: New acridone-4-carboxylic acid derivatives as potential inhibitors of hepatitis C virus infection.
abstract: 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 microM to 20 microM) 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.
authors.affiliation: Institute of Biochemistry and Biophysics PAS, Pawinskiego 5a, 02-106 Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Stankiewicz-Drogon
authors.forename: Larisa G
authors.initials: LG
authors.lastname: Palchykovska
authors.forename: Valentina G
authors.initials: VG
authors.lastname: Kostina
authors.forename: Inna V
authors.initials: IV
authors.lastname: Alexeeva
authors.forename: Anatoly D
authors.initials: AD
authors.lastname: Shved
authors.forename: Anna M
authors.initials: AM
authors.lastname: Boguszewska-Chachulska
mesh_terms: D054831:Acridones / Q000138:chemical synthesis / Q000494:pharmacology*; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D005470:Fluorometry; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D020128:Inhibitory Concentration 50; D020365:RNA Helicases / Q000037:antagonists & inhibitors / Q000378:metabolism; D012328:RNA Viruses / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D054831:Acridones; D000998:Antiviral Agents; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D012321:DNA-Directed RNA Polymerases; D020365:RNA Helicases