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

Wright, C.W., Addee-Kyereme, J., Breen, A.G., Brown, J.E., Cox, M.F., Croft, S.L., Gokcek, Y., Kendrick, H., Phillips, Roger M. and Pollet, P.L. (2001) Synthesis and evaluation of cryptolepine analogues for their potential as new antimalarial agents. Journal of Medicinal Chemistry, 44 (19). pp. 3187-3194. ISSN 0022-2623

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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.

Item Type: Article
Subjects: R Medicine > RM Therapeutics. Pharmacology
Schools: School of Applied Sciences
Related URLs:
Depositing User: Roger Phillips
Date Deposited: 14 May 2015 09:10
Last Modified: 14 May 2015 09:10
URI: http://eprints.hud.ac.uk/id/eprint/24481

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