Differences in anti-malarial activity of 4-aminoalcohol quinoline enantiomers and investigation of the presumed underlying mechanism of action

Malaria Journal

Research

Nicolas Taudon¹  Camille Desgrouas¹  Alexia Jonet²  Pascal Sonnet²  Catherine Mullié² 

[1] Laboratoire de Bioanalyse et Pharmacocinétique, UMR-MD3, Université de la Méditerranée, Institut de Recherche Biomédicale des Armées, Allée du Médecin Colonel Eugène Jamot, Parc du Pharo, BP 60109, 13262, Marseille Cedex 07, France;Laboratoire des Glucides, UMR-CNRS 6219, UFR de Pharmacie, 1 rue des Louvels, 80037, Amiens Cedex 1, France;

关键词: Plasmodium falciparum;    Anti-malarial activity;    β-haematin;    Quinoline;    Enantiomer;    Mefloquine;   

DOI  :  10.1186/1475-2875-11-65

 received in 2011-11-29, accepted in 2012-03-08,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundA better anti-malarial efficiency and lower neurotoxicity have been reported for mefloquine (MQ) (+)- enantiomer. However, the importance of stereoselectivity remains poorly understood as the anti-malarial activity of pure enantiomer MQ analogues has never been described. Building on these observations, a series of enantiopure 4-aminoalcohol quinoline derivatives has previously been synthesized to optimize the efficiency and reduce possible adverse effects. Their in vitro activity on Plasmodium falciparum W2 and 3D7 strains is reported here along with their inhibition of β-haematin formation and peroxidative degradation of haemin, two possible mechanisms of action of anti-malarial drugs.ResultsThe (S)-enantiomers of this series of 4-aminoalcohol quinoline derivatives were found to be at least as effective as both chloroquine (CQ) and MQ. The derivative with a 5-carbon side-chain length was the more efficient on both P. falciparum strains. (R )-enantiomers displayed an activity decreased by 2 to 15-fold as compared to their (S) counterparts. The inhibition of β-haematin formation was significantly stronger with all tested compounds than with MQ, irrespective of the stereochemistry. Similarly, the inhibition of haemin peroxidation was significantly higher for both (S) and (R)-enantiomers of derivatives with a side-chain length of five or six carbons than for MQ and CQ.ConclusionsThe prominence of stereochemistry in the anti-malarial activity of 4-aminoalcohol quinoline derivatives is confirmed. The inhibition of β-haematin formation and haemin peroxidation can be put forward as presumed mechanisms of action but do not account for the stereoselectivity of action witnessed in vitro.

【 授权许可】

CC BY   
© Mullié et al; licensee BioMed Central Ltd. 2012