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

Malaria Journal

Research

Aurélie Pascual¹  Pascal Sonnet²  Catherine Mullié²  Alexia Jonet²  Patrice Agnamey³  Nicolas Taudon⁴  Camille Degrouas⁵ 

[1] Département d’Infectiologie de Terrain, Unité de Parasitologie, Institut de Recherche Biomédicale des Armées, Marseille, France;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;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;Laboratoire de Parasitologie et Mycologie, Amiens University Hospital, Avenue Laënnec, 80054, Amiens, France;UMR-MD3, Institut de Recherche Biomédicale des Armées, BP 73, 91223, Brétigny-sur-Orge, France;UMR-MD3, Institut de Recherche Biomédicale des Armées, Faculté de Pharmacie, Aix-Marseille Université, 27 Bd Jean Moulin CS30064, 13385, Marseille cedex 5, France;

关键词: Malaria;    Plasmodium falciparum;    Plasmodium berghei;    in vivo;    Anti-malarial activity;    Quinoline;    Enantiomer;    Dihydroartemisinin;    Isobologram;    Combination;   

DOI  :  10.1186/1475-2875-13-407

 received in 2014-07-31, accepted in 2014-10-10,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundAs 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.MethodsScreening 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.ResultsA 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.ConclusionsThe 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.

【 授权许可】

CC BY   
© Mullié et al.; licensee BioMed Central Ltd. 2014