title: Antimalarial acridines: synthesis, in vitro activity against P. falciparum and interaction with hematin.
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 IC(50)0.07 microM, close to that of chloroquine itself, and that of the three chloroquine-resistant strains better than chloroquine with IC(50)0.3 microM. These acridine derivatives inhibited the formation of beta-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.
authors.affiliation: Equipe 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.
authors.forename: Lucie
authors.initials: L
authors.lastname: Guetzoyan
authors.forename: Xiao-Min
authors.initials: XM
authors.lastname: Yu
authors.forename: Florence
authors.initials: F
authors.lastname: Ramiandrasoa
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Pethe
authors.forename: Christophe
authors.initials: C
authors.lastname: Rogier
authors.forename: Bruno
authors.initials: B
authors.lastname: Pradines
authors.forename: Thierry
authors.initials: T
authors.lastname: Cresteil
authors.forename: Martine
authors.initials: M
authors.lastname: Perrée-Fauvet
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Mahy
mesh_terms: D000609:Aminoacridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006427:Hemin / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D016778:Malaria, Falciparum / Q000188:drug therapy*; D013058:Mass Spectrometry; D010963:Plasmodium falciparum / Q000254:growth & development*; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship
chemical_list: D000609:Aminoacridines; D000962:Antimalarials; D006427:Hemin