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Total Synthesis of a Noricumazole A Library and Evaluation of HCV Inhibition

Authors

  • Dr. Jenny Barbier,

    1. Institut für Organische Chemie und Zentrum für Biomolekulare Wirkstoffe (BMWZ), Leibniz Universität Hannover, Schneiderberg 1B, 30167 Hannover (Germany), Fax: (+49) 511-762-3011
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  • Dr. Jens Wegner,

    1. Institut für Organische Chemie und Zentrum für Biomolekulare Wirkstoffe (BMWZ), Leibniz Universität Hannover, Schneiderberg 1B, 30167 Hannover (Germany), Fax: (+49) 511-762-3011
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  • Dr. Stefan Benson,

    1. Institut für Organische Chemie und Zentrum für Biomolekulare Wirkstoffe (BMWZ), Leibniz Universität Hannover, Schneiderberg 1B, 30167 Hannover (Germany), Fax: (+49) 511-762-3011
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  • Dr. Juliane Gentzsch,

    1. TWINCORE, Zentrum für Experimentelle und Klinische Infektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover (Germany)
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  • Prof. Dr. Thomas Pietschmann,

    1. TWINCORE, Zentrum für Experimentelle und Klinische Infektionsforschung GmbH, Feodor-Lynen-Str. 7, 30625 Hannover (Germany)
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  • Prof. Dr. Andreas Kirschning

    Corresponding author
    1. Institut für Organische Chemie und Zentrum für Biomolekulare Wirkstoffe (BMWZ), Leibniz Universität Hannover, Schneiderberg 1B, 30167 Hannover (Germany), Fax: (+49) 511-762-3011
    • Institut für Organische Chemie und Zentrum für Biomolekulare Wirkstoffe (BMWZ), Leibniz Universität Hannover, Schneiderberg 1B, 30167 Hannover (Germany), Fax: (+49) 511-762-3011
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Abstract

The total synthesis of 16 new ion channel inhibitors derived from noricumazole A, a secondary metabolite from the myxobacterium Sorangium cellulosum, is reported. Particular focus of library design is put on stereochemical permutations in the central region (C9 and C11), the oxazole moiety and the side chain at C4 of the isochromanone moiety. Noricumazole A and all new noricumazole derivatives were tested in an assay system with inhibitory effect on the hepatitis C virus (HCV) life cycle. Most of them are moderate to strong HCV inhibitors (350 nM–6 nM) but also exert pronounced cytotoxicity. In contrast, the thiazole analogue of noricumazole A is a strong HCV inhibitor with only moderate cytotoxic property. It may become a lead structure with a good therapeutic index (CC50/IC50) of greater than 10.

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