Indolone-N-oxide derivatives: in vitro activity against fresh clinical isolates of Plasmodium falciparum, stage specificity and in vitro interactions with established antimalarial drugs

Abstract

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 [(3)H]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 (IC(50)) 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.