Synthesis of New Acridone Derivatives, Inhibitors of NS3 Helicase, Which Efficiently and Specifically Inhibit Subgenomic HCV Replication

Anna Stankiewicz-Drogon, Bernd Dörner, Thomas Erker (Korresp. Autor*in), Anna M. Boguszewska-Chachulska

    Veröffentlichungen: Beitrag in FachzeitschriftArtikelPeer Reviewed


    A new goup of acridone derivatives, obtained by reaction of acridone-4-carboxylic acid derivatives with aromatic amines, was tested to determine the inhibitory properties toward the NS3 helicase of hepatitis C virus (HCV). Six compounds inhibited the NS3 helicase at low concentrations (IC50 from 1.5 to 20 mu M). The acridone derivatives probably act via intercalation into double-stranded nucleic acids with a strong specificity for double-stranded RNA, although an interaction with the enzyme cannot be excluded. Testing in the subgenomic HCV replicon system revealed that compounds 10 and 13 are efficient RNA replication inhibitors, with EC50 of 3.5 and 1 mu M and therapeutic indexes of > 28 and 20, respectively. Compound 16, with EC50 <1 mu M and TI > 1000, is extremely specific and practically noncytotoxic at the concentrations tested, proving that the acridone derivatives may be regarded as potential antiviral agents. Although the mechanism of action of 16 in the replicon system remains unclear, it is the key lead compound for further development of anti-HCV drugs.
    Seiten (von - bis)3117-3126
    FachzeitschriftJournal of Medicinal Chemistry
    PublikationsstatusVeröffentlicht - 2010

    ÖFOS 2012

    • 3012 Pharmazie, Pharmakologie, Toxikologie