title: Natural products from Garcinia brasiliensis as Leishmania protease inhibitors.
abstract: The infections by protozoans of the genus Leishmania are a major worldwide health problem, with high endemicity in developing countries. The drugs of choice for the treatment of leishmaniasis are the pentavalent antimonials, which cause renal and cardiac toxicity. As part of a search for new drugs against leishmaniasis, we evaluated the in vitro Leishmania protease inhibition activity of extracts (hexanic, ethyl-acetate, and ethanolic) and fukugetin, a bioflavonoid purified from the ethyl-acetate extract of the pericarp of the fruit of Garcinia brasiliensis, a tree native to Brazilian forests. The isolated compound was characterized by using spectral analyses with nuclear magnetic resonance, mass spectroscopy, ultraviolet, and infrared techniques. The ethyl-acetate extract and the compound fukugetin showed significant activity as inhibitors of Leishmania's proteases, with mean (±SD) IC(50) (50% inhibition concentration of protease activity) values of 15.0±1.3 μg/mL and 3.2±0.5 μM/mL, respectively, characterizing a bioguided assay. In addition, this isolated compound showed no activity against promastigote and amastigote forms of L. (L.) amazonensis and mammalian cells. These results suggest that fukugetin is a potent protease inhibitor of L. (L.) amazonensis and does not cause toxicity in mammalian or Leishmania cells in vitro. This study provides new perspectives on the development of novel drugs that have leishmanicidal activity obtained from natural products and that target the parasite's proteases.
authors.affiliation: Department of Pharmacy, Laboratory of Phytochemistry and Medicinal Chemistry, Federal University of Alfenas, Minas Gerais, Brazil. ivan.farma@yahoo.com.br
authors.forename: Ivan O
authors.initials: IO
authors.lastname: Pereira
authors.forename: Diego M
authors.initials: DM
authors.lastname: Assis
authors.forename: Maria A
authors.initials: MA
authors.lastname: Juliano
authors.forename: Rodrigo L O R
authors.initials: RL
authors.lastname: Cunha
authors.forename: Clara L
authors.initials: CL
authors.lastname: Barbieri
authors.forename: Luis V S
authors.initials: LV
authors.lastname: do Sacramento
authors.forename: Marcos J
authors.initials: MJ
authors.lastname: Marques
authors.forename: Marcelo H
authors.initials: MH
authors.lastname: dos Santos
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D001938:Brazil; D005638:Fruit / Q000737:chemistry; D029760:Garcinia / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D007891:Leishmania / Q000187:drug effects* / Q000201:enzymology*; D007896:Leishmaniasis / Q000469:parasitology; D010447:Peptide Hydrolases / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats
chemical_list: D000981:Antiprotozoal Agents; D010936:Plant Extracts; D011480:Protease Inhibitors; D015800:Protozoan Proteins; D010447:Peptide Hydrolases