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

M Chen; L Zhai; S B Christensen; T G Theander; A Kharazmi

doi:10.1128/AAC.45.7.2023-2029.2001

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

M Chen, L Zhai, S B Christensen, T G Theander, A Kharazmi

Centre for Medical Parasitology

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

207 Citationer (Scopus)

Abstract

Udgivelsesdato: 2001-Jul

Originalsprog	Engelsk
Tidsskrift	Antimicrobial Agents and Chemotherapy
Vol/bind	45
Udgave nummer	7
Sider (fra-til)	2023-9
Antal sider	6
ISSN	0066-4804
DOI	https://doi.org/10.1128/AAC.45.7.2023-2029.2001
Status	Udgivet - 2001

Bibliografisk note

Keywords: Animals; Antiprotozoal Agents; Chalcone; Chalcones; Electron Transport; Enzyme Inhibitors; Leishmania donovani; Leishmania major; Mitochondria; NADH Dehydrogenase; Permeability; Phenylacetates; Succinate Cytochrome c Oxidoreductase; Succinate Dehydrogenase

Adgang til dokumentet

10.1128/AAC.45.7.2023-2029.2001

Citationsformater

@article{a092be80a0d611dd86a6000ea68e967b,

title = "Inhibition of fumarate reductase in Leishmania major and L. donovani by chalcones",

abstract = "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.",

author = "M Chen and L Zhai and Christensen, {S B} and Theander, {T G} and A Kharazmi",

note = "Keywords: Animals; Antiprotozoal Agents; Chalcone; Chalcones; Electron Transport; Enzyme Inhibitors; Leishmania donovani; Leishmania major; Mitochondria; NADH Dehydrogenase; Permeability; Phenylacetates; Succinate Cytochrome c Oxidoreductase; Succinate Dehydrogenase",

year = "2001",

doi = "10.1128/AAC.45.7.2023-2029.2001",

language = "English",

volume = "45",

pages = "2023--9",

journal = "Antimicrobial Agents and Chemotherapy",

issn = "0066-4804",

publisher = "American Society for Microbiology",

number = "7",

}

TY - JOUR

T1 - Inhibition of fumarate reductase in Leishmania major and L. donovani by chalcones

AU - Chen, M

AU - Zhai, L

AU - Christensen, S B

AU - Theander, T G

AU - Kharazmi, A

N1 - Keywords: Animals; Antiprotozoal Agents; Chalcone; Chalcones; Electron Transport; Enzyme Inhibitors; Leishmania donovani; Leishmania major; Mitochondria; NADH Dehydrogenase; Permeability; Phenylacetates; Succinate Cytochrome c Oxidoreductase; Succinate Dehydrogenase

PY - 2001

Y1 - 2001

N2 - 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.

AB - 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.

U2 - 10.1128/AAC.45.7.2023-2029.2001

DO - 10.1128/AAC.45.7.2023-2029.2001

M3 - Journal article

C2 - 11408218

SN - 0066-4804

VL - 45

SP - 2023

EP - 2029

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

IS - 7

ER -