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

C W Wright, Jonathan Addae-Kyereme, Anthony G Breen, John E Brown, Marlene F Cox, S L Croft, Yaman Gökçek, Howard Kendrick, R M Phillips, Pamela L Pollet

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194 Citations (Scopus)


The 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 beta-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 (DeltaT(m) value) or toxicity in the mouse-malaria model.

Original languageEnglish
Pages (from-to)3187-94
Number of pages8
JournalJournal of Medicinal Chemistry
Issue number19
Publication statusPublished - 13 Sep 2001
Externally publishedYes


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