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Antimicrobial Agents and Chemotherapy, July 2001, p. 2023-2029, Vol. 45, No. 7
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.7.2023-2029.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Inhibition of Fumarate Reductase in Leishmania major and L. donovani by Chalcones

Ming Chen,1,2,* Lin Zhai,1 Søren Brøgger Christensen,3 Thor G. Theander,4 and Arsalan Kharazmi1

Centre for Medical Parasitology, Department of Clinical Microbiology, University Hospital of Copenhagen,1 Statens Seruminstitut,2 Department of Medicinal Chemistry, The Royal Danish School of Pharmacy,3 and Institute for Medical Microbiology and Immunology, University of Copenhagen,4 Copenhagen, Denmark

Received 6 February 2001/Returned for modification 5 March 2001/Accepted 17 April 2001

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 (IC50) of licochalcone A for these enzymes were at least 20 times higher than that for FRD. The IC50 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.

* Corresponding author. Mailing address: Department of Clinical Microbiology, 7806, Rigshospitalet, Tagensvej 20, DK-2200 Copenhagen N, Denmark. Phone: (45) 35 45 77 38. Fax: (45) 35 45 68 31. E-mail: cmcmp{at}rh.dk.

Antimicrobial Agents and Chemotherapy, July 2001, p. 2023-2029, Vol. 45, No. 7
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.7.2023-2029.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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