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01.12.2012 | Research | Ausgabe 1/2012 Open Access

Malaria Journal 1/2012

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

Zeitschrift:
Malaria Journal > Ausgabe 1/2012
Autoren:
Catherine Mullié, Alexia Jonet, Camille Desgrouas, Nicolas Taudon, Pascal Sonnet
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1475-2875-11-65) contains supplementary material, which is available to authorized users.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

CM carried out the β-haematin and peroxidation studies, performed the statistical analysis and drafted the manuscript. AJ carried out the synthesis of 4-aminoalcohol quinoline derivatives. CD performed the Plasmodium falciparum susceptibility assays. NT participated to the Plasmodium falciparum susceptibility assays and helped to draft the manuscript. PS participated in the design and coordination of the study and helped to draft the manuscript. All authors read and approved the final manuscript.

Abstract

Background

A 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.

Results

The (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.

Conclusions

The 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.
Zusatzmaterial
Additional file 1: Peroxidative degradation of haemin at pH 7.0. The data provided represent the mean values (± SD) of the peroxidative degradation of haemin performed at pH 7.0 along with the statistical analysis. (DOC 38 KB)
12936_2011_2032_MOESM1_ESM.DOC
Authors’ original file for figure 1
12936_2011_2032_MOESM2_ESM.pdf
Literatur
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