Synthesis of some cryptolepine analogues, assessment of their antimalarial and cytotoxic activities, and consideration of their antimalarial mode of action.
Onyeibor, Onyeka;
Croft, Simon L;
Dodson, Hilary I;
Feiz-Haddad, Mohammad;
Kendrick, Howard;
Millington, Nicola J;
Parapini, Silvia;
Phillips, Roger M;
Seville, Scott;
Shnyder, Steven D;
+2 more...Taramelli, Donatella;
Wright, Colin W;
(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, 48 (7).
pp. 2701-2709.
ISSN 0022-2623
DOI: https://doi.org/10.1021/jm040893w
Permanent Identifier
Use this Digital Object Identifier when citing or linking to this resource.
A series of analogues of cryptolepine (1) have been synthesized and evaluated for their in vitro antiplasmodial and cytotoxic properties. The IC(50) values of several compounds (11a, 11k-m, 11o, 13) against Plasmodium falciparum (strain K1) were <0.1 muM, 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 (ED(90) = 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 beta-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 (r(2) = 0.0781) suggesting that the potent antimalarial activity of compounds such as 15 involves other mechanisms in addition to the inhibition of hemozoin formation.