title: Leishmanicidal metabolites from Cochliobolus sp., an endophytic fungus isolated from Piptadenia adiantoides (Fabaceae).
abstract: Protozoan parasites belonging to genera Leishmania and Trypanosoma are the etiological agents of severe neglected tropical diseases (NTDs) that cause enormous social and economic impact in many countries of tropical and sub-tropical areas of the world. In our screening program for new drug leads from natural sources, we found that the crude extract of the endophytic fungus Cochliobolus sp. (UFMGCB-555) could kill 90% of the amastigote-like forms of Leishmania amazonensis and inhibit by 100% Ellman's reagent reduction in the trypanothione reductase (TryR) assay, when tested at 20 microg mL(-1). UFMGCB-555 was isolated from the plant Piptadenia adiantoides J.F. Macbr (Fabaceae) and identified based on the sequence of the internally transcribed spacer (ITS) regions of its ribosomal DNA. The chromatographic fractionation of the extract was guided by the TryR assay and resulted in the isolation of cochlioquinone A and isocochlioquinone A. Both compounds were active in the assay with L. amazonensis, disclosing EC(50) values (effective concentrations required to kill 50% of the parasite) of 1.7 microM (95% confidence interval = 1.6 to 1.9 microM) and 4.1 microM (95% confidence interval = 3.6 to 4.7 microM), respectively. These compounds were not active against three human cancer cell lines (MCF-7, TK-10, and UACC-62), indicating some degree of selectivity towards the parasites. These results suggest that cochlioquinones are attractive lead compounds that deserve further investigation aiming at developing new drugs to treat leishmaniasis. The findings also reinforce the role of endophytic fungi as an important source of compounds with potential to enter the pipeline for drug development against NTDs.
authors.affiliation: Laboratório de Química de Produtos Naturais, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Fernanda Fraga
authors.initials: FF
authors.lastname: Campos
authors.forename: Luiz Henrique
authors.initials: LH
authors.lastname: Rosa
authors.forename: Betania Barros
authors.initials: BB
authors.lastname: Cota
authors.forename: Rachel Basques
authors.initials: RB
authors.lastname: Caligiorne
authors.forename: Ana Lúcia Teles
authors.initials: AL
authors.lastname: Rabello
authors.forename: Tânia Maria Almeida
authors.initials: TM
authors.lastname: Alves
authors.forename: Carlos Augusto
authors.initials: CA
authors.lastname: Rosa
authors.forename: Carlos Leomar
authors.initials: CL
authors.lastname: Zani
mesh_terms: D017954:Africa South of the Sahara; D000818:Animals; D001203:Ascomycota / Q000235:genetics; D016227:Benzoquinones / Q000302:isolation & purification; D001943:Breast Neoplasms / Q000469:parasitology; D045744:Cell Line, Tumor; D002489:Central America; D017931:DNA Primers; D004271:DNA, Fungal / Q000235:genetics; D004275:DNA, Ribosomal / Q000235:genetics; D007887:Fabaceae / Q000382:microbiology* / Q000469:parasitology*; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000469:parasitology; D007894:Leishmania mexicana / Q000302:isolation & purification*; D008545:Melanoma / Q000469:parasitology; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013020:South America; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors; D014329:Tropical Climate; D014345:Trypanosoma / Q000302:isolation & purification*; D014349:Trypanosoma cruzi / Q000201:enzymology / Q000302:isolation & purification; D014944:World Health Organization
chemical_list: D016227:Benzoquinones; D017931:DNA Primers; D004271:DNA, Fungal; D004275:DNA, Ribosomal; D011994:Recombinant Proteins; C066134:cochlioquinone A; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D002785:Sterol O-Acyltransferase