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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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.

Original languageEnglish
Pages (from-to)2701-2709
Number of pages9
JournalJournal of Medicinal Chemistry
Volume48
Issue number7
Early online date3 Mar 2005
DOIs
Publication statusPublished - 7 Apr 2005
Externally publishedYes

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Antimalarials
Hemin
Parasitemia
Chloroquine
Plasmodium falciparum
Vacuoles
Inhibitory Concentration 50
Toxicity
Parasites
Food
hemozoin

Cite this

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. ; Taramelli, Donatella ; Wright, Colin W. / Synthesis of Some Crytpolepine Analogues, Assessment of Their Antimalarial and Cytotoxic Activities, and Consideration of Their Antimalarial Mode of Action. In: Journal of Medicinal Chemistry. 2005 ; Vol. 48, No. 7. pp. 2701-2709.
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title = "Synthesis of Some Crytpolepine Analogues, Assessment of Their Antimalarial and Cytotoxic Activities, and Consideration of Their Antimalarial Mode of Action",
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.",
author = "Onyeka Onyeibor and Croft, {Simon L.} and Dodson, {Hilary I.} and Mohammad Feiz-Haddad and Howard Kendrick and Millington, {Nicola J.} and Silvia Parapini and Phillips, {Roger M.} and Scott Seville and Shnyder, {Steven D.} and Donatella Taramelli and Wright, {Colin W.}",
year = "2005",
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Onyeibor, O, Croft, SL, Dodson, HI, Feiz-Haddad, M, Kendrick, H, Millington, NJ, Parapini, S, Phillips, RM, Seville, S, Shnyder, SD, Taramelli, D & Wright, CW 2005, 'Synthesis of Some Crytpolepine 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. https://doi.org/10.1021/jm040893w

Synthesis of Some Crytpolepine 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.; Taramelli, Donatella; Wright, Colin W.

In: Journal of Medicinal Chemistry, Vol. 48, No. 7, 07.04.2005, p. 2701-2709.

Research output: Contribution to journalArticle

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T1 - Synthesis of Some Crytpolepine Analogues, Assessment of Their Antimalarial and Cytotoxic Activities, and Consideration of Their Antimalarial Mode of Action

AU - Onyeibor, Onyeka

AU - Croft, Simon L.

AU - Dodson, Hilary I.

AU - Feiz-Haddad, Mohammad

AU - Kendrick, Howard

AU - Millington, Nicola J.

AU - Parapini, Silvia

AU - Phillips, Roger M.

AU - Seville, Scott

AU - Shnyder, Steven D.

AU - Taramelli, Donatella

AU - Wright, Colin W.

PY - 2005/4/7

Y1 - 2005/4/7

N2 - 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.

AB - 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.

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JF - Journal of Medicinal Chemistry

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