IN-VITRO INHIBITION OF LIVER FORMS OF THE RODENT MALARIA PARASITE PLASMODIUM-BERGHEI BY NAPHTHYLISOQUINOLINE ALKALOIDS STRUCTURE-ACTIVITY-RELATIONSHIPS OF DIONCOPHYLLINE-A AND DIONCOPHYLLINE-C AND ANCISTROCLADINE

Naphthylisoquinoline alkaloids are derived from Dioncophyllaceae and A ncistrocladaceae species and comprise a new class of promising antimal arials with a demonstrated potential against asexual erythrocytic Plas modium falciparum and P. berghei stages in vitro. We report herein the pronounced activity of pure naphthylisoquinoline alkaloids against ex oerythrocytic malaria parasites. P. berghei-infected human hepatoma ce lls (Hep G2) were incubated with culture medium containing selected al kaloids at 10 mu g/ml. The most active compounds, showing inhibitory a ctivity of more than 40%, were dioncophylline A (compound 1), dioncoph yllacine A (compound 6), and ancistrobarterine A (compound 12). For st ructure-activity investigations of dioncophyllines A (compound 1) and C (compound 3) and ancistrocladine (compound 7) a selection of their a nalogs from natural or synthetic sources was examined. Dioncophylleine A (compound 16), 5'-O-demethyl-8-O-methyl-7-epi-dioncophylline A (com pound 17), N-formyl-8-O-methyl-dioncophylline C (compound 21), and N-f ormyl-8-O-benzoyldioncophylline C (compound 24) were found to display high levels of activity as well, although the former two compounds cau sed damage to the host-cell monolayers. As naphthylisoquinoline alkalo ids are also highly active against blood forms of Plasmodium spp., the y should be regarded as lead compounds for further development as drug s against erythrocytic and exoerythrocytic stages of Plasmodium spp.