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 naphthylisoquinoline alkaloids against asexual blood stages of Plasmodium falciparum (NF 54, clone A1A9) and P. berghei (Anka) were studied in vitro. Three of the alkaloids [7-epi-dioncophylline A (8b), dioncolactone A (4), and 5'-O-demethyl-8-O-methyl-7-epidioncophylline A (11)] displayed good activities against both parasites, with median inhibitory concentrations (IC50) of 1-5 micrograms/ml. Dioncophylline C (2), however, was even better, with IC50 of 0.014 microgram/ml (P. falciparum) and 0.015 microgram/ml (P. berghei) and therefore regarded as a promising lead for studies of structure-activity relationships. The free N- and 8-OH-functions were shown 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 experiments with derivatives of ancistrocladine (1) show that, in contrast to 2, N-derivatization of this alkaloid leads to increased activity against P. falciparum.