title: Differences in anti-malarial activity of 4-aminoalcohol quinoline enantiomers and investigation of the presumed underlying mechanism of action.
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.
authors.affiliation: Laboratoire des Glucides, UMR-CNRS 6219, UFR de Pharmacie, 1 rue des Louvels, 80037 Amiens Cedex 1, France. catherine.mullie@u-picardie.fr
authors.forename: Catherine
authors.initials: C
authors.lastname: Mullié
authors.forename: Alexia
authors.initials: A
authors.lastname: Jonet
authors.forename: Camille
authors.initials: C
authors.lastname: Desgrouas
authors.forename: Nicolas
authors.initials: N
authors.lastname: Taudon
authors.forename: Pascal
authors.initials: P
authors.lastname: Sonnet
mesh_terms: D000605:Amino Alcohols / Q000737:chemistry* / Q000494:pharmacology; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D004351:Drug Resistance; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D006420:Hemeproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006427:Hemin / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000605:Amino Alcohols; D000962:Antimalarials; D006420:Hemeproteins; D011804:Quinolines; C020753:hemozoin; D006427:Hemin