Synthesis and evaluation of cryptolepine analogues for their potential as new antimalarial agents

The indoloquinoline alkaloid cryptolepine 1 has potent in vitro antiplasmod ial activity, but it is also a DNA intercalator with cytotoxic properties. We have shown that the antiplasmodial mechanism of 1 is likely to be due, a t least in part, to a chloroquine-like action that does not depend on inter calation into DNA. A number of substituted analogues of 1 have been prepare d that have potent activities against both chloroquine-sensitive and chloro quine-resistant strains of Plasmodium falciparum and also have in common wi th chloroquine the inhibition of beta -hematin formation in a cell-free sys tem. Several compounds also displayed activity against Plasmodium berghei i n mice, the most potent being 2,7-dibromocryptolepine 8, which suppressed p arasitemia by 89% as compared to untreated infected controls at a dose of 1 2.5 mg kg(-1) day(-1) ip. No correlation was observed between in vitro cyto toxicity and the effect of compounds on the melting point of DNA (DeltaT(m) value) or toxicity in the mouse-malaria model.