Naphthylisoquinoline alkaloids against malaria: evaluation of the curative potentials of dioncophylline C and dioncopeltine A against Plasmodium berghei in vivo

Abstract

Naphthylisoquinoline alkaloid-containing extracts from species of the families Dioncophyllaceae and Ancistrocladaceae and purified alkaloids derived therefrom were shown to exhibit antiparasitic activity in Plasmodium berghei-infected mice. Several extracts and alkaloids, especially dioncophylline C and dioncopeltine A, isolated from Triphyophyllum peltatum (Dioncophyllaceae), displayed high levels of activity. Dioncopeltine A was able to suppress parasitemia almost totally, while dioncophylline C cured infected mice completely after oral treatment with 50 mg kg of body weight(-1) day(-1) for 4 days without noticeable toxic effects. Analysis of the dose-response relationship of dioncophylline C revealed a 50% effective dosage (ED50) of 10.71 mg kg(-1) day(-1) under these conditions. Although four daily treatments with 50 mg kg(-1) day(-1) are needed to achieve radical cure, one oral dose is sufficient to kill 99.6% of the parasites. Intravenous application of dioncophylline C is even more effective, with an ED50 of 1.90 mg kg(-1) day(-1) and no noticeable toxic effects. The compound also suppressed more established P. berghei infections when orally applied at day 3 after infection. Both dioncopeltine A and dioncophylline C are active against the chloroquine-resistant P. berghei Anka CRS parasites. Sustained release of these compounds at 20 mg kg(-1) day(-1) by implanted miniosmotic pumps exhibited curative effects. The naphthylisoquinoline alkaloids are therefore promising new antimalarial agents.

Natural products as antiparasitic drugs

“…When tested in vitro and in vivo against Plasmodium falciparum they show remarkable activity. This was also the case against Leishmania and Trypanosoma species (Francois et al 1997a(Francois et al , 1997b. Extracts from Triphophyllum peltatum (Dioncophyllaceae) led to the isolation of dioncophylline B (structure 12, Fig.…”

“…1) and dioncophylline C (structure 13, Fig. 1), both exhibiting high antiplasmodial activity (Francois et al 1997b). Dioncophylline C cured malaria-infected mice completely after a 4-day oral treatment with 50 mg kg -1 day -1 without noticeable toxic effects.…”

Biotransformation and pharmacokinetics of the antiplasmodial naphthylisoquinoline alkaloid dioncophylline A

“…The naphthylisoquinoline alkaloids represent a new and promising class of lead structures of such novel antimalarial drug candidates (François et al 1996(François et al , 1997a(François et al , 1997bBringmann and Feineis 2000;Bringmann and Rummey 2003). These alkaloids comprise a remarkable group of natural products, characterized by a rotationally hindered and thus stereogenic biaryl axis coupling the naphthalene and isoquinoline moieties (Bringmann and Pokorny 1995;Bringmann et al 1998a).…”

Ancistroheynine B and two further 7,3′-coupled naphthylisoquinoline alkaloids from Ancistrocladus heyneanus Wall.

“…Alkaloid 7 exhibited moderate antiplasmodial activities against the K1 strain of Plasmodium falciparum (resistant to chloroquine and pyrimethamine), slightly weaker than the known compounds 3 and 6 (Bringmann et al, 2004). These findings, although not reaching the good results of other naphthylisoquinolines (Bringmann et al, 2003a(Bringmann et al, , 2003bFrançois et al, 1997François et al, , 1999, gave an important contribution to our ongoing QSAR (Quantitative Structure-Activity Relationship) investigations (Bringmann and Rummey, 2003c;Stiefl et al, 2003).…”