Synthesis of Some Crytpolepine Analogues, Assessment of Their Antimalarial and Cytotoxic Activities, and Consideration of Their Antimalarial Mode of Action

Onyeka Onyeibor, Simon L. Croft, Hilary I. Dodson, Mohammad Feiz-Haddad, Howard Kendrick, Nicola J. Millington, Silvia Parapini, Roger M. Phillips, Scott Seville, Steven D. Shnyder, Donatella Taramelli, Colin W. Wright

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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 μM, 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 β-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.

Original languageEnglish
Pages (from-to)2701-2709
Number of pages9
JournalJournal of Medicinal Chemistry
Issue number7
Early online date3 Mar 2005
Publication statusPublished - 7 Apr 2005
Externally publishedYes


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