title: 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: OBJECTIVE
  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.
authors.affiliation: Unité Mixte de Recherche 198, Institut de Recherche pour le Développement-Organisation de Coordination pour la lutte contre les Endémies en Afrique Centrale (OCEAC), Yaoundé, Cameroon.
authors.forename: Rachida
authors.initials: R
authors.lastname: Tahar
authors.forename: Livia
authors.initials: L
authors.lastname: Vivas
authors.forename: Leonardo
authors.initials: L
authors.lastname: Basco
authors.forename: Eloise
authors.initials: E
authors.lastname: Thompson
authors.forename: Hany
authors.initials: H
authors.lastname: Ibrahim
authors.forename: Jérémie
authors.initials: J
authors.lastname: Boyer
authors.forename: Françoise
authors.initials: F
authors.lastname: Nepveu
mesh_terms: D000328:Adult; D000962:Antimalarials / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology; D002163:Cameroon; D002738:Chloroquine / Q000494:pharmacology; D004347:Drug Interactions; D004351:Drug Resistance; D005260:Female; D006801:Humans; D019271:Hypoxanthine / Q000378:metabolism; D007211:Indoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D016778:Malaria, Falciparum / Q000469:parasitology; D008297:Male; D009589:Nitrogen Oxides / Q000737:chemistry / Q000494:pharmacology; D010084:Oxidation-Reduction; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development / Q000302:isolation & purification / Q000378:metabolism
chemical_list: C570801:6-(4-chlorophenyl)-7H-(1,3)dioxolo(4,5-f)indol-7-one-5-oxide; D000962:Antimalarials; D037621:Artemisinins; D007211:Indoles; D009589:Nitrogen Oxides; C015388:nitrones; D019271:Hypoxanthine; C039060:artenimol; D002738:Chloroquine