Ebselen : an antimalarial compound active against ferredoxin-NADP+ reductase of Plasmodium falciparum

Ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one)is a seleno-organic compound that has been extensively studied as an anti-inflammatory drug. It reacts with thiol groups forming selenylsulphide bonds and it has been reported to inhibit a variety of enzymes involved in different processes1. Moreover, ebselen has been shown possesse an antimalarial activity in vitro against P. falciparum strains in the asexual stages. Since this compounds displayed no cytotoxic effects on human epatocyte, it is of interest for the design of antimalarial drugs2. The effect of ebselen on ferredoxin-NADP+ reductase of Plasmodium falciparum (PfFNR), an enzyme located in the apicoplast of the parasite3, has been investigated. Ebselen was found to slowly and irreversibly inhibit PfFNR targeting one or more Cys residue of the enzyme. Spectrofluorimetric studies pointed out that ebselen promotes the release of prosthetic group FAD. PfFNR was found to be particularly sensitive to inactivation in comparison to similanr flavoenzymes. The compound is 9-fold less active against the omologue FNR from spinach leaf, while Mycobacterium tuberculosis FprA, a ferredoxin-reductase structurally unrelated to plant type FNRs, turned out to be completely insensitive to this inhibitor, These preliminary data suggest that PfFNR could be a potential target of the antiplasmodial activity of ebselen.1. Schewe T. (1995) Gen. Pharmac. 26 (6): 1153-1169 2. Huter A. M. et al. (1989) Parasitol Res. 75 (5): 353-60 3. Seeber F. et al. (2005) Curr. Pharm. Des. 11, 3159-3172