Xanthones as antimalarial agents; studies of a possible mode of action

fThe 4-aminoquinoline naphthoquine (NQ) and the thiazine dye methylene blue (MB) have potent in vitro efficacies against Plasmodium falciparum, but susceptibility data for P. vivax are limited. The species-and stage-specific ex vivo activities of NQ and MB were assessed using a modified schizont maturation assay on clinical field isolates from Papua, Indonesia, where multidrugresistant P. falciparum and P. vivax are prevalent. Both compounds were highly active against P. falciparum . Stage-specific drug susceptibility assays revealed significantly greater IC 50 s in parasites exposed at the trophozoite stage than at the ring stage for NQ in P. falciparum (26.5 versus 5.1 nM, P ‫؍‬ 0.021) and P. vivax (341.6 versus 6.5 nM, P ‫؍‬ 0.021) and for MB in P. vivax (10.1 versus 1.6 nM, P ‫؍‬ 0.010). The excellent ex vivo activities of NQ and MB against both P. falciparum and P. vivax highlight their potential utility for the treatment of multidrug-resistant malaria in areas where both species are endemic.

Section: Discussionsupporting

confidence: 79%

Potent Ex Vivo Activity of Naphthoquine and Methylene Blue against Drug-Resistant Clinical Isolates of Plasmodium falciparum and Plasmodium vivax

Wirjanata

Sebayang

Chalfein

et al. 2015

“…The ability of the EA derivatives to interfere with heme aggregation was determined in 20 mM sodium phosphate (pH 5.2) as described by Ignatushchenko et al (19). A 10 mM stock solution of hemin chloride in 0.1 M NaOH was prepared freshly and incubated at 37°C for at least 1 h prior to use.…”

Section: Drugs and Chemicalsmentioning

confidence: 99%

Compounds Structurally Related to Ellagic Acid Show Improved Antiplasmodial Activity

Sturm

Ying

Zimmermann

et al. 2009

The cancer chemopreventive agent ellagic acid (EA) is a known inhibitor of glutathione S-transferases (GSTs) and possesses antiplasmodial activities in the upper-nanomolar range. In the recent drug development approach, the properties of the active site of Plasmodium falciparum GST were exploited for inhibitor design by introducing one or two additional hydroxyl groups into EA, yielding flavellagic acid (FEA) and coruleoellagic acid (CEA), respectively. Indeed, the inhibition of P. falciparum GST was improved with the increasing hydrophilicity of the planar polyaromatic ring system. Studying the effects of the two compounds on the central redox enzymes of Plasmodium revealed that glutathione reductase and thioredoxin reductase also are inhibited in the lower-micromolar range. Both compounds had strong antiplasmodial activity in the lower-nanomolar range and were particularly effective against chloroquine (CQ)-resistant P. falciparum strains. Neither FEA nor CEA showed cytotoxic effects on human cells. This was supported by negligible changes in transcript levels and enzyme activities of redox enzymes in human A549 cells upon treatment with the compounds. In Plasmodium, however, CEA treatment resulted in a marked downregulation of most antioxidant genes studied and impaired mainly the trophozoite stage of the parasites. In addition, EA, CEA, and FEA were found to strongly inhibit in vitro heme aggregation. In vitro and preliminary in vivo studies indicated that, compared to CQ, CEA is a slowly acting compound and is able to significantly improve the survival of Plasmodium berghei-infected mice. We conclude that FEA and CEA are promising antimalarial compounds that deserve to be studied further.

“…We have demonstrated that selected hydroxyxanthones form soluble complexes with heme and prevent the precipitation of heme in aqueous solution under the mildly acidic conditions of the digestive vacuole at pH 5.2 (14). In a recent study of the interaction between heme and 4,5-dihydroxyxanthone, a model that features carbonyl-iron coordination, -stacking of the coplanar aromatic molecules, and hydrogen bonding between the drug's hydroxyl substituents and the propionate side chains of heme was found to be consistent with the proton nuclear magnetic resonance (NMR) data (17).…”

mentioning

confidence: 99%

Optimization of Xanthones for Antimalarial Activity: the 3,6-Bis-ω-Diethylaminoalkoxyxanthone Series

Kelly

Winter

Peyton

et al. 2002

Self Cite

Hydroxyxanthones have been identified as novel antimalarial agents. The compounds are believed to exert their activity by complexation to heme and inhibition of hemozoin formation. Modification of the xanthone structure was pursued to improve their antimalarial activity. Attachment of R-groups bearing protonatable nitrogen atoms was conducted to enhance heme affinity through ionic interactions with the propionate side chains of the metalloporphyrin and to facilitate drug accumulation in the parasite food vacuole. A series of 3,6-bis--diethylaminoalkoxyxanthones with side chains ranging from 2 to 8 carbon atoms were prepared and evaluated. Measurement of heme affinity for each of the derivatives revealed a strong correlation (R 2 ‫؍‬ 0.97) between affinity and antimalarial potency. The two most active compounds in the series contained 5-and 6-carbon side chains and exhibited low nanomolar 50% inhibitory concentration (IC 50 ) values against strains of chloroquine-susceptible and multidrug-resistant Plasmodium falciparum in vitro. Both of these xanthones exhibit stronger heme affinity (8.26 ؋ 10 5 and 9.02 ؋ 10 5 M ؊1 , respectively) than either chloroquine or quinine under similar conditions and appear to complex heme in a unique manner.Malaria represents the most deadly parasitic human disease, despite countless efforts to eradicate or control it. Each year, it threatens roughly 40% of the world's population, infects over 200 million people, and claims 2 million lives-primarily children under 5 years of age (32, 36). To make matters worse, treatment of malaria is becoming increasingly more difficult due to the emergence of multidrug-resistant strains of Plasmodium falciparum, causative agent of the most severe form of the disease (32). As a result, there is a pressing need to develop novel antimalarial agents.The Plasmodium parasite infects erythrocytes and digests hemoglobin within an acidic food vacuole for salvage of critically needed amino acids (21). This proteolytic process results in the release of toxic heme, which is sequestered into an insoluble nontoxic substance known as hemozoin, or more commonly as "malaria pigment" (1,22,27). The classical antimalarial quinolines, quinine and chloroquine, are believed to act via complexation to heme in a manner that perturbs hemozoin formation (7,10,23,26,30).Hydroxyxanthones have been identified by us as a novel class of antimalarial compounds with activity against multidrug-resistant Plasmodium parasites (34,35). We have demonstrated that selected hydroxyxanthones form soluble complexes with heme and prevent the precipitation of heme in aqueous solution under the mildly acidic conditions of the digestive vacuole at pH 5.2 (14). In a recent study of the interaction between heme and 4,5-dihydroxyxanthone, a model that features carbonyl-iron coordination, -stacking of the coplanar aromatic molecules, and hydrogen bonding between the drug's hydroxyl substituents and the propionate side chains of heme was found to be consistent with the proton nuclear magnetic resona...