Synthesis and evaluation of cryptolepine analogues for their potential as new antimalarial agents.
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| Abstract |
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.
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| Authors | C W Wright, J Addae-Kyereme, A G Breen, J E Brown, M F Cox, S L Croft, Y Gökçek, H Kendrick, R M Phillips, P L Pollet |
| Journal | Journal of medicinal chemistry (J Med Chem) Vol. 44 Issue 19 Pg. 3187-94 (Sep 13 2001) ISSN: 0022-2623 [Print] United States |
| PMID | 11543688 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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