Synthesis and Evaluation of Cryptolepine Analogues for Their Potential as New Antimalarial Agents

The indoloquinoline alkaloid cryptolepine <BO>1</BO> has potent in vitro antiplasmodial activity, but it is also a DNA intercalator with cytotoxic properties. We have shown that the antiplasmodial mechanism of <BO>1</BO> is likely to be due, at least in part, to a chloroquine-like action that does not depend on intercalation into DNA. A number of substituted analogues of <BO>1 </BO>have been prepared that have potent activities against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum and also have in common with chloroquine the inhibition of β-hematin formation in a cell-free system. Several compounds also displayed activity against Plasmodium berghei in mice, the most potent being 2,7-dibromocryptolepine <BO>8</BO>, which suppressed parasitemia by 89% as compared to untreated infected controls at a dose of 12.5 mg kg^-1 day^-1 ip. No correlation was observed between in vitro cytotoxicity and the effect of compounds on the melting point of DNA (ΔT<INF>m</INF> value) or toxicity in the mouse−malaria model.