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

FEBS Letters

Riscoe, Michael K.²  Hinrichs, David J.¹  Bächinger, Hans Peter³  Winter, R.W.¹  Ignatushchenko, Marina V.² 

[1] Medical Research Service, 151-0, Department of Veterans' Affairs Medical Center, 3710 SW US Veterans Hospital Road, Portland, OR 97035, USA;Department of Biochemistry and Molecular Biology, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR 97201, USA;Shriners Hospital for Crippled Children, 3101 SW Sam Jackson Park Road, Portland, OR 97201, USA

关键词: Malaria;    Chemotherapy;    Plasmodium falciparum;    Digestive vacuole;    Heme polymerization;    Xanthone;   

DOI  :  10.1016/S0014-5793(97)00405-5

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

We recently demonstrated that 2,3,4,5,6-pentahydroxyxanthone (X5) inhibits the in vitro growth of both chloroquine-sensitive and multidrug-resistant strains of P. falciparum. To study the molecular basis of its antimalarial action, we tested X5 and selected hydroxyxanthone analogs as inhibitors of in vitro heme polymerization in a low ionic strength phosphate solution at mildly acidic pH. We found that addition of 1 Eq. of X5 resulted in complete inhibition of polymerization in this system whereas addition of up to 40 Eqs. of standard antimalarial compounds (chloroquine, primaquine, quinacrine, artemisinin and methylene blue) had no such effect although these compounds did co-precipitate with heme. The antimalarial potency of the hydroxyxanthones correlated well with their ability to inhibit in vitro heme polymerization in our assay, suggesting that these compounds exert their antimalarial action by preventing hemozoin formation. Based on the observed structure–activity relationships, we propose a model displaying possible interactions between hydroxyxanthones and heme.

【 授权许可】

Unknown