Synthesis of some cryptolepine 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 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.

• Authors: 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 48 Issue 7 Pg. 2701-9 (Apr 07 2005) ISSN: 0022-2623 [Print] United States
• PMID: 15801861 (Publication Type: Journal Article)

Chemical References

• Alkaloids
• Antimalarials
• Antineoplastic Agents
• Hemeproteins
• Indole Alkaloids
• Indoles
• Quinolines
• hemozoin
• cryptolepine

Topics

• Algorithms
• Alkaloids (chemical synthesis, chemistry, pharmacology)
• Animals
• Antimalarials (chemical synthesis, chemistry, pharmacology)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Female
• Hemeproteins (antagonists & inhibitors, chemical synthesis)
• Indole Alkaloids
• Indoles (chemical synthesis, chemistry, pharmacology)
• Malaria (drug therapy)
• Mice
• Mice, Inbred BALB C
• Plasmodium berghei
• Plasmodium falciparum (drug effects)
• Quinolines (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship