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    Synthesis of some cryptolepine analogues, assessment of their antimalarial and cytotoxic activities, and consideration of their antimalarial mode of action.

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    Publication date
    2005
    Author
    Wright, Colin W.
    Onyeibor, O.
    Phillips, Roger M.
    Shnyder, Steven D.
    Croft, S.L.
    Dodson, Hilary I.
    Keyword
    Cryptolepine analogues
    Antimalarial mode of action
    Antiplasmodial activity
    Dose-dependent suppression of parasitemia
    Halogens
    Antimalarial and cytotoxic activities
    Peer-Reviewed
    Yes
    
    Metadata
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    Abstract
    A series of analogues of cryptolepine (1) have been synthesized and evaluated for their in vitro antiplasmodial and cytotoxic properties. The IC50 values of several compounds (11a, 11k¿m, 11o, 13) against Plasmodium falciparum (strain K1) were <0.1 ¿M, 5¿10-fold lower than that of 1 but their cytotoxicities were only 2¿4 times greater than that of 1. Compounds with a halogen in the quinoline ring and a halogen or a nitro group in the indole ring have enhanced antiplasmodial activity. In mice infected with P. berghei, the 7-bromo-2-chloro (11k) and 2-bromo-7-nitro (13) derivatives of 1 suppressed parasitemia by >90% at doses of 25 mg kg-1 day-1 with no apparent toxicity to the mice. 2,7-Dibromocryptolepine (15) was evaluated at several dose levels, and a dose-dependent suppression of parasitemia was seen (ED90 = 21.6 mg kg-1 day-1). The antimalarial mode of action of 1 appears to be similar to that of chloroquine and involves the inhibition of hemozoin formation. A number of analogues were assessed for their effects on the inhibition of ß-hematin (hemozoin) formation, and the results were compared with their antiplasmodial activities having taken account of their predicted accumulation into the acidic parasite food vacuole. No correlation was seen (r2 = 0.0781) suggesting that the potent antimalarial activity of compounds such as 15 involves other mechanisms in addition to the inhibition of hemozoin formation.
    URI
    http://hdl.handle.net/10454/3215
    Version
    No full-text available in the repository
    Citation
    Wright, C.W., Phillips, R.M., Shnyder, S.D. and Onyeibor, O. et al. (2005). Synthesis of some cryptolepine analogues, assessment of their antimalarial and cytotoxic activities, and consideration of their antimalarial mode of action. Journal of Medicinal Chemistry. Vol. 48, No. 7, pp. 2701-2709.
    Link to publisher’s version
    http://dx.doi.org/10.1021/jm040893w
    Type
    Article
    Collections
    Life Sciences Publications

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