Inhibition of fumarate reductase in Leishmania major and L. donovani by chalcones.
Our previous studies have shown that chalcones exhibit potent antileishmanial and antimalarial activities in vitro and in vivo. Preliminary studies showed that these compounds destroyed the ultrastructure of Leishmania parasite mitochondria and inhibited the respiration and the activity of mitochondrial dehydrogenases of Leishmania parasites. The present study was designed to further investigate the mechanism of action of chalcones, focusing on the parasite respiratory chain. The data show that licochalcone A inhibited the activity of fumarate reductase (FRD) in the permeabilized Leishmania major promastigote and in the parasite mitochondria, and it also inhibited solubilized 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 activities of succinate dehydrogenase (SDH), NADH dehydrogenase (NDH), and succinate- and NADH-cytochrome c reductases in the parasite mitochondria, the 50% inhibitory concentrations (IC(50)) of licochalcone A for these enzymes were at least 20 times higher than that for FRD. The IC(50) of licochalcone A for SDH and NDH in human peripheral blood mononuclear cells were at least 70 times higher than that for FRD. These findings indicate that FRD, one of the enzymes 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 antiprotozoal drugs.
Chen
M
M
Centre for Medical Parasitology, Department of Clinical Microbiology, University Hospital of Copenhagen, Copenhagen, Denmark. cmcmp@rh.dk
Zhai
L
L
Christensen
S B
SB
Theander
T G
TG
Kharazmi
A
A
D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology; D002599:Chalcone / Q000031:analogs & derivatives / Q000494:pharmacology*; D047188:Chalcones; D004579:Electron Transport / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007893:Leishmania donovani / Q000187:drug effects* / Q000201:enzymology; D018320:Leishmania major / Q000187:drug effects* / Q000201:enzymology; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D009245:NADH Dehydrogenase / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D010648:Phenylacetates / Q000494:pharmacology; D013384:Succinate Cytochrome c Oxidoreductase / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism
D000981:Antiprotozoal Agents; D047188:Chalcones; D004791:Enzyme Inhibitors; D010648:Phenylacetates; C023699:3-methoxyphenylacetic acid; D002599:Chalcone; D013384:Succinate Cytochrome c Oxidoreductase; D013385:Succinate Dehydrogenase; D009245:NADH Dehydrogenase; C070840:licochalcone A