TY - JOUR
T1 - Potentiation of an antimalarial oxidant drug
AU - Winter, R. W.
AU - Ignatushchenko, Marina
AU - Ogundahunsi, Olumide A.T.
AU - Cornell, Kenneth A.
AU - Oduola, Ayoade M.J.
AU - Hinrichs, David J.
AU - Riscoe, Michael K.
PY - 1997/7
Y1 - 1997/7
N2 - 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 (XS). 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.
AB - 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 (XS). 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.
UR - http://www.scopus.com/inward/record.url?scp=0030878175&partnerID=8YFLogxK
U2 - 10.1128/aac.41.7.1449
DO - 10.1128/aac.41.7.1449
M3 - Article
C2 - 9210664
AN - SCOPUS:0030878175
SN - 0066-4804
VL - 41
SP - 1449
EP - 1454
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
IS - 7
ER -