title: Potentiation of an antimalarial oxidant drug.
abstract: In a previous report we described the synergistic antimalarial interaction between two structurally similar compounds, rufigallol and exifone. To explain this phenomenon, we proposed that exifone is transformed inside the parasitized erythrocyte into a xanthone with potent antimalarial properties. We speculated that the transformation process was induced by the prooxidant activity of rufigallol. On the basis of this model we hypothesized that exifone would act synergistically with other oxidant drugs. In the present study we have found a similar synergistic interaction between exifone and ascorbic acid (vitamin C) against both chloroquine-susceptible and multidrug-resistant strains of Plasmodium falciparum. The prooxidant activity of ascorbic acid against Plasmodium-infected erythrocytes is believed to result from an intraerythrocytic Fenton reaction occurring in the acidic food vacuole of the parasite. The hydroxyl radicals produced during this process are believed to attack exifone, which undergoes cyclodehydration to become 2,3,4,5,6-pentahydroxyxanthone (X5). Evidence presented to support this "xanthone hypothesis" includes the demonstration that the exifone ==> X5 transformation occurs readily in vitro under mildly acidic conditions in the presence of iron, ascorbic acid, and oxygen.
authors.affiliation: Medical Research Service, Department of Veterans' Affairs Medical Center, Portland, Oregon 97201, USA.
authors.forename: R W
authors.initials: RW
authors.lastname: Winter
authors.forename: M
authors.initials: M
authors.lastname: Ignatushchenko
authors.forename: O A
authors.initials: OA
authors.lastname: Ogundahunsi
authors.forename: K A
authors.initials: KA
authors.lastname: Cornell
authors.forename: A M
authors.initials: AM
authors.lastname: Oduola
authors.forename: D J
authors.initials: DJ
authors.lastname: Hinrichs
authors.forename: M K
authors.initials: MK
authors.lastname: Riscoe
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D001205:Ascorbic Acid / Q000627:therapeutic use*; D001577:Benzophenones / Q000627:therapeutic use*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D001577:Benzophenones; C052932:exifone; D001205:Ascorbic Acid; D010100:Oxygen