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.
François
G
G
Laboratorium voor Protozoölogie, Prins Leopold Instituut voor Tropische Geneeskunde, Antwerpen, Belgium.
Timperman
G
G
Holenz
J
J
Aké Assi
L
L
Geuder
T
T
Maes
L
L
Dubois
J
J
Hanocq
M
M
Bringmann
G
G
D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured / Q000187:drug effects; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D051379:Mice; D009284:Naphthols / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D010962:Plasmodium berghei / Q000187:drug effects* / Q000254:growth & development; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D013329:Structure-Activity Relationship
D000470:Alkaloids; D000962:Antimalarials; D007546:Isoquinolines; D009284:Naphthols; C103717:dioncophylline C