Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 17, Issue 23, Pages 8032-8039Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2009.10.005
Keywords
Antimalarial; Plasmodium falciparum; Aminoacridine; beta-Hematin
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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 mu M, close to that of chloroquine itself, and that of the three chloroquine-resistant strains better than chloroquine with IC50 <= 0.3 mu M. 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. (c) 2009 Elsevier Ltd. All rights reserved.
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