NAPHTHYLISOQUINOLINE ALKALOIDS EXHIBIT STRONG GROWTH-INHIBITING ACTIVITIES AGAINST PLASMODIUM-FALCIPARUM AND P-BERGHEI IN-VITRO - STRUCTURE-ACTIVITY-RELATIONSHIPS OF DIONCOPHYLLINE-C

The growth-inhibiting activities of naturally occurring naphthylisoqui noline alkaloids against asexual blood stages of Plasmodium falciparum (NF 54, clone A1A9) and P. berghei (Anka) were studied in vitro. Thre e of the alkaloids [7-epi-dioncophylline A (8b), dioncolactone A (4), and 5'-O-demethyl-8-O-methyl-7-epi-dioncophylline A (11)] displayed go od activities against both parasites, with median inhibitory concentra tions (IC50) of 1-5 mu g/ml. Dioncophylline C (2), however, was even b etter, with IC50 of 0.014 mu g/ml (P. falciparum) and 0.015 mu g/ml (P . berghei) and therefore regarded as a promising lead for studies of s tructure-activity relationships. The free N- and 8-OH-functions were s hown to be prerequisites for the outstanding activity of this molecule against P. falciparum, the presence of at least one free phenolic OH- function appearing to be essential for any activity. Initial experimen ts with derivatives of ancistrocladine (1) show that, in contrast to 2 , N-derivatization of this alkaloid leads to increased activity agains t P. falciparum.