%0 Journal Article
%9 ACL : Articles dans des revues avec comité de lecture répertoriées par l'AERES
%A Tahar, Rachida
%A Vivas, L.
%A Basco, Leonardo
%A Thompson, E.
%A Ibrahim, H.
%A Boyer, J.
%A Nepveu, F.
%T Indolone-N-oxide derivatives : in vitro activity against fresh clinical isolates of Plasmodium falciparum, stage specificity and in vitro interactions with established antimalarial drugs
%D 2011
%L PAR00008074
%G ENG
%J Journal of Antimicrobial Chemotherapy
%@ 0305-7453
%K antimalarial drugs ; drug resistance ; chloroquine ; artemisinin ; redox
%M ISI:000295989500020
%N 11
%P 2566-2572
%R 10.1093/jac/dkr320
%U https://www.documentation.ird.fr/hor/PAR00008074
%V 66
%W Horizon (IRD)
%X Objectives: Indolone-N-oxides are characterized by the presence of a highly reactive pharmacophore, the nitrone moiety (C=N+-O-), which undergoes oxidation-reduction reactions. The aims of the present study were to: (i) evaluate the in vitro activity of the parent compound, designated as compound 1, against 34 fresh clinical isolates of Plasmodium falciparum; (ii) compare the activity of compound 1 with that of chloroquine and dihydroartemisinin to assess the potential for cross-resistance; (iii) investigate drug interactions of indolone-N-oxides with standard antimalarials; and (iv) determine the stage-dependent activity of indolone-N-oxides. Methods: In vitro antimalarial activity was evaluated against clinical isolates collected from Cameroonian patients by the [H-3]hypoxanthine incorporation assay. In vitro interactions between compound 1 or another analogue, compound 4, and established antimalarial drugs were assessed by the fixed ratio method. Stage specificity was evaluated by light microscopy using highly synchronized P. falciparum cultures. Results: The geometric mean 50% inhibitory concentration (IC50) of compound 1 was 48.6 nM. Its activity did not differ between the chloroquine-susceptible and the chloroquine-resistant isolates. There was no correlation between chloroquine and compound 1 responses (r=0.015; P>0.05), but the in vitro responses of compound 1 and dihydroartemisinin were significantly and positively correlated (r=0.444; P<0.05). No significant in vitro interaction was observed between indolone-N-oxide derivatives and established antimalarial drugs (artemisinin and its derivatives, chloroquine, amodiaquine, quinine and mefloquine). Compound 1 and compound 4, as well as artesunate, inhibited parasite maturation at the ring stage. Conclusions: These findings suggest that other indolone-N-oxide derivatives with more potent activity than the parent compound may hold promise as antimalarials in the future.
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