| Summary: | <p>Abstract</p> <p>Background</p> <p>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 <it>in vitro </it>activity on <it>Plasmodium falciparum </it>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.</p> <p>Results</p> <p>The (<it>S</it>)-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 <it>P. falciparum </it>strains. (<it>R </it>)-enantiomers displayed an activity decreased by 2 to 15-fold as compared to their (<it>S</it>) 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 (<it>S</it>) and (<it>R</it>)-enantiomers of derivatives with a side-chain length of five or six carbons than for MQ and CQ.</p> <p>Conclusions</p> <p>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 <it>in vitro</it>.</p>
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