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

Research output: Contribution to journalArticle

157 Citations (Scopus)

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.

LanguageEnglish
Pages3187-94
Number of pages8
JournalJournal of Medicinal Chemistry
Volume44
Issue number19
DOIs
Publication statusPublished - 13 Sep 2001
Externally publishedYes

Fingerprint

Chloroquine
Antimalarials
Intercalating Agents
Nucleic Acid Denaturation
Plasmodium berghei
Parasitemia
Cell-Free System
DNA
Plasmodium falciparum
Alkaloids
Malaria
cryptolepine
In Vitro Techniques

Cite this

Wright, C. W., Addae-Kyereme, J., Breen, A. G., Brown, J. E., Cox, M. F., Croft, S. L., ... Pollet, P. L. (2001). Synthesis and evaluation of cryptolepine analogues for their potential as new antimalarial agents. Journal of Medicinal Chemistry, 44(19), 3187-94. https://doi.org/10.1021/jm010929+
Wright, C W ; Addae-Kyereme, Jonathan ; Breen, Anthony G ; Brown, John E ; Cox, Marlene F ; Croft, S L ; Gökçek, Yaman ; Kendrick, Howard ; Phillips, R M ; Pollet, Pamela L. / Synthesis and evaluation of cryptolepine analogues for their potential as new antimalarial agents. In: Journal of Medicinal Chemistry. 2001 ; Vol. 44, No. 19. pp. 3187-94.
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Wright, CW, Addae-Kyereme, J, Breen, AG, Brown, JE, Cox, MF, Croft, SL, Gökçek, Y, Kendrick, H, Phillips, RM & Pollet, PL 2001, 'Synthesis and evaluation of cryptolepine analogues for their potential as new antimalarial agents', Journal of Medicinal Chemistry, vol. 44, no. 19, pp. 3187-94. https://doi.org/10.1021/jm010929+

Synthesis and evaluation of cryptolepine analogues for their potential as new antimalarial agents. / Wright, C W; Addae-Kyereme, Jonathan; Breen, Anthony G; Brown, John E; Cox, Marlene F; Croft, S L; Gökçek, Yaman; Kendrick, Howard; Phillips, R M; Pollet, Pamela L.

In: Journal of Medicinal Chemistry, Vol. 44, No. 19, 13.09.2001, p. 3187-94.

Research output: Contribution to journalArticle

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AU - Wright, C W

AU - Addae-Kyereme, Jonathan

AU - Breen, Anthony G

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AU - Cox, Marlene F

AU - Croft, S L

AU - Gökçek, Yaman

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AU - Phillips, R M

AU - Pollet, Pamela L

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N2 - 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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KW - Indoles

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KW - Mice

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KW - Plasmodium berghei

KW - Plasmodium falciparum/drug effects

KW - Quinolines

KW - Structure-Activity Relationship

KW - Tumor Cells, Cultured

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