Synthesis and evaluation of cryptolepine analogues for their potential as new antimalarial agents.
Wright, Colin W. Addae-Kyereme, Jonathan A. Breen, Anthony G. Brown, John E. Cox, Marlene F. Croft, S.L. Gokcek, Yaman Kendrick, H. Phillips, Roger M. Pollet, Pamela L.
Wright, Colin W.
Addae-Kyereme, Jonathan A.
Breen, Anthony G.
Brown, John E.
Cox, Marlene F.
Croft, S.L.
Gokcek, Yaman
Kendrick, H.
Phillips, Roger M.
Pollet, Pamela L.
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2001
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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 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.
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Wright, C.W., Addae-Kyereme, J., Breen, A.G., Brown, J.E. and Cox, M.F. et al. (2001). Synthesis and evaluation of cryptolepine analogues for their potential as new antimalarial agents. Journal of Medicinal Chemistry. Vol. 44, No. 19, pp. 3187-3194.
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