Inhibition of fumarate reductase in Leishmania major and L-donovani by chalcones

Our previous studies have shown that chalcones exhibit potent antileishmani al and antimalarial activities in vitro and in vivo. Preliminary studies sh owed that these compounds destroyed the ultrastructure of Leishmania parasi te mitochondria and inhibited the respiration and the activity of mitochond rial dehydrogenases of Leishmania parasites. The present study was designed to further investigate the mechanism of action of chalcones, focusing on t he parasite respiratory chain. The data show that licochalcone A inhibited the activity of fumarate reductase (FRD) in the permeabilized Leishmania ma jor promastigote and in the parasite mitochondria, and it also inhibited so lubilized FRD and a purified FRD from L. donovani. Two other chalcones, 2,4 -dimethoxy-4'-allyloxychalcone (24m4ac) and 2,4-dimethoxy-4'-butoxychalcone (24mbc), also exhibited inhibitory effects on the activity of solubilized FRD in L. major promastigotes. Although licochalcone A inhibited the activi ties of succinate dehydrogenase (SDH), NADH dehydrogenase (NDH), and succin ate and NADH-cytochrome c reductases in the parasite mitochondria, the 50% inhibitory concentrations (IC50) of licochalcone A for these enzymes were a t least 20 times higher than that for FRD, The IC50 of licochalcone A for S DH and NDH in human peripheral blood mononuclear cells were at least 70 tim es higher than that for FRD. These findings indicate that FRD, one of the e nzymes of the parasite respiratory chain, might be the specific target for the chalcones tested. Since FRD exists in the Leishmania parasite and does not exist in mammalian cells, it could be an excellent target for antiproto zoal drugs.