| Abstract
| - A series of analogues of cryptolepine (1) have been synthesized and evaluated for their in vitroantiplasmodial 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 thatof 1 but their cytotoxicities were only 2−4 times greater than that of 1. Compounds with ahalogen in the quinoline ring and a halogen or a nitro group in the indole ring have enhancedantiplasmodial activity. In mice infected with P. berghei, the 7-bromo-2-chloro (11k) and2-bromo-7-nitro (13) derivatives of 1 suppressed parasitemia by >90% at doses of 25 mg kg-1day-1 with no apparent toxicity to the mice. 2,7-Dibromocryptolepine (15) was evaluated atseveral dose levels, and a dose-dependent suppression of parasitemia was seen (ED90 = 21.6mg kg-1 day-1). The antimalarial mode of action of 1 appears to be similar to that of chloroquineand involves the inhibition of hemozoin formation. A number of analogues were assessed fortheir effects on the inhibition of β-hematin (hemozoin) formation, and the results were comparedwith their antiplasmodial activities having taken account of their predicted accumulation intothe acidic parasite food vacuole. No correlation was seen (r2 = 0.0781) suggesting that thepotent antimalarial activity of compounds such as 15 involves other mechanisms in additionto the inhibition of hemozoin formation.
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