Jozimine A ('dimeric' dioncophylline A), a non-natural michellamine analog with high antimalarial activity

The synthesis of jozimine A, the first non-natural dimer of a naturally occurring monomeric naphthylisoquinoline alkaloid, is described, starting from dioncophylline A, as isolated from Triphophyllum peltatum, resp. prepared by total synthesis. It is the first dimeric naphthylisoquinoline alkaloid that displays distinct antimalarial activity (IC50 = 0.075 μg/ml) against asexual erythrocytic stages of Plasmodium falciparum, which even exceeds the activity of its monomeric precursor, dioncophylline A (IC50 = 1.44 μg/ml), and thus constitutes a novel type of antimalarial quateraryls.
Jozimine A (4), the first artificial ‘dimer’ of a natural naphthylisoquinoline alkaloid, was prepared. Compared with its ‘monomeric’ precursor, dioncophylline A, 4 shows greatly enhanced antimalarial activity.