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

By Colin W. Wright, Jonathan A. Addae-Kyereme, Anthony G. Breen, John E. Brown, Marlene F. Cox, S.L. Croft, Yaman Gokcek, H. Kendrick, Roger M. Phillips and Pamela L. Pollet


NoThe indoloquinoline alkaloid cryptolepine 1 has potent in vitro antiplasmodial 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, at least in part, to a chloroquine-like action that does not depend on intercalation into DNA. A number of substituted analogues of 1 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 ß-hematin formation in a cell-free system. Several compounds also displayed activity against Plasmodium berghei in mice, the most potent being 2,7-dibromocryptolepine 8, 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 (¿Tm value) or toxicity in the mouse¿malaria model

Topics: Infection, Protozoal disease, Malaria, DNA, Cryptolepine analogues, Antimalarial agents.
Year: 2001
DOI identifier: 10.1021/jm010929
OAI identifier:
Provided by: Bradford Scholars
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