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.

Synthesis of some cryptolepine analogues, assessment of their antimalarial and cytotoxic activities and consideration of their mode of action / O. Onyeibor, S.L. Croft, H.I. Dodson, M. Feiz-Haddad, H. Kendrick, H. Kendrick, S. Parapini, R.M. Phillips, S. Seville, S. Shnyder, D. Taramelli, C.W. Wright. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 48:7(2005), pp. 2701-2709. [10.1021/jm040893w]

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

S. Parapini;D. Taramelli
Penultimo
;
2005

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 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.
Settore MED/04 - Patologia Generale
2005
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/17291
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