Antimalarial acridines: Synthesis,in vitro activity against P. falciparum and interaction with hematin |
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Authors: | Lucie Guetzoyan Xiao-Min Yu Florence Ramiandrasoa Stéphanie Pethe Christophe Rogier Bruno Pradines Thierry Cresteil Martine Perrée-Fauvet Jean-Pierre Mahy |
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Institution: | 1. Équipe de Chimie Bioorganique et Bioinorganique, Institut de Chimie Moléculaire et des Matériaux d’Orsay, Bât. 420, CNRS UMR 8182, Univ Paris-Sud, 91405 Orsay Cedex, France;2. Unité de Recherche en Biologie et Epidémiologie Parasitaires, Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes, UMR 6236, Institut de Médecine Tropicale du Service des Armées, Bd Charles Livon, Parc Le Pharo, 13998 Marseille Armées, France;3. Ciblothèque cellulaire, Institut de Chimie des Substances Naturelles, CNRS, Gif sur Yvette, France |
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Abstract: | A series of acridine derivatives were synthesised and their in vitro antimalarial activity was evaluated against one chloroquine-susceptible strain (3D7) and three chloroquine-resistant strains (W2, Bre1 and FCR3) of Plasmodium falciparum. Structure–activity relationship showed that two positives charges as well as 6-chloro and 2-methoxy substituents on the acridine ring were required to exert a good antimalarial activity. The best compounds possessing these features inhibited the growth of the chloroquine-susceptible strain with an IC50 ? 0.07 μM, close to that of chloroquine itself, and that of the three chloroquine-resistant strains better than chloroquine with IC50 ? 0.3 μM. These acridine derivatives inhibited the formation of β-hematin, suggesting that, like CQ, they act on the haem crystallization process. Finally, in vitro cytotoxicity was also evaluated upon human KB cells, which showed that one of them 9-(6-ammonioethylamino)-6-chloro-2-methoxyacridinium dichloride 1 displayed a promising antimalarial activity in vitro with a quite good selectivity index versus mammalian cell on the CQ-susceptible strain and promising selectivity on other strains. |
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