title: Enantiomerically pure amino-alcohol quinolines: in vitro anti-malarial activity in combination with dihydroartemisinin, cytotoxicity and in vivo efficacy in a Plasmodium berghei mouse model.
abstract: BACKGROUND
  As resistance to marketed anti-malarial drugs continues to spread, the need for new molecules active on Plasmodium falciparum-resistant strains grows. Pure (S) enantiomers of amino-alcohol quinolines previously displayed a good in vitro anti-malarial activity. Therefore, a more thorough assessment of their potential clinical use through a rodent model and an in vitro evaluation of their combination with artemisinin was undertaken.
  
  
  METHODS
  Screening on a panel of P. falciparum clones with varying resistance profiles and regional origins was performed for the (S)-pentyl and (S)-heptyl substituted quinoline derivatives, followed by an in vitro assessment of their combination with dihydroartemisinin (DHA) on the 3D7 clone and an in vivo assay in a mouse model infected with Plasmodium berghei. Their haemolytic activity was also determined.
  
  
  RESULTS
  A steady anti-malarial activity of the compounds tested was found, whatever the resistance profile or the regional origin of the strain. (S)-quinoline derivatives were at least three times more potent than mefloquine (MQ), their structurally close parent. The in vitro combination with DHA yielded an additive or synergic effect for both that was as good as that of the DHA/MQ combination. In vivo, survival rates were similar to those of MQ for the two compounds at a lower dose, despite a lack of clearance of the parasite blood stages. A 50% haemolysis was observed for concentrations at least 1,000-fold higher than the antiplasmodial IC50s.
  
  
  CONCLUSIONS
  The results obtained make those two (S)-amino-alcohol quinoline derivatives good candidates for the development of new artemisinin-based combination therapy (ACT), hopefully with fewer neurologic side effects than those currently marketed ACT, including MQ.
authors.affiliation: Equipe Théra - Laboratoire de Glycochimie, des Antimicrobiens et des Agroressources (LG2A) FRE-CNRS 3517, Université de Picardie Jules Verne, 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: Nicolas
authors.initials: N
authors.lastname: Taudon
authors.forename: Camille
authors.initials: C
authors.lastname: Degrouas
authors.forename: Alexia
authors.initials: A
authors.lastname: Jonet
authors.forename: Aurélie
authors.initials: A
authors.lastname: Pascual
authors.forename: Patrice
authors.initials: P
authors.lastname: Agnamey
authors.forename: Pascal
authors.initials: P
authors.lastname: Sonnet
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use* / Q000633:toxicity; D037621:Artemisinins / Q000494:pharmacology* / Q000627:therapeutic use* / Q000633:toxicity; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004912:Erythrocytes / Q000187:drug effects; D005260:Female; D006461:Hemolysis; D020128:Inhibitory Concentration 50; D008288:Malaria / Q000188:drug therapy*; D008807:Mice, Inbred BALB C; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D011804:Quinolines / Q000494:pharmacology* / Q000627:therapeutic use* / Q000633:toxicity; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D011804:Quinolines; C039060:artenimol