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.