title: Triterpenoids as inhibitors of erythrocytic and liver stages of Plasmodium infections.
abstract: Bioassay-guided fractionation of the methanol extract of Momordica balsamina led to the isolation of two new cucurbitane-type triterpenoids, balsaminol F (1) and balsaminoside B (2), along with the known glycosylated cucurbitacins, cucurbita-5,24-diene-3β,23(R)-diol-7-O-β-D-glucopyranoside (3) and kuguaglycoside A (4). Compound 1 was acylated yielding two new triesters, triacetylbalsaminol F (5) and tribenzoylbalsaminol F (6). The structures were elucidated based on spectroscopic methods including 2D-NMR experiments (COSY, HMQC, HMBC and NOESY). Compounds 1-6, were evaluated for their antimalarial activity against the erythrocytic stages of the Plasmodium falciparum chloroquine-sensitive strain 3D7 and the chloroquine-resistant clone Dd2. Assessment of compounds (1-3 and 5, 6) activity against the liver stage of Plasmodium berghei was also performed, measuring the luminescence intensity in Huh-7 cells infected with a firefly luciferase-expressing P. berghei line, PbGFP-Luc(con). Active compounds were shown to inhibit the parasite's intracellular development rather than its ability to invade hepatic cells. Toxicity of compounds (1-3 and 5, 6) was assessed on the same cell line and on mouse primary hepatocytes through the fluorescence measurement of cell confluency. Furthermore, toxicity of compounds 1-6 towards human cells was also investigated in the MCF-7 breast cancer cell line, showing that they were not toxic or exhibited weak toxicity. In blood stages of P. falciparum, compounds 1-5 displayed antimalarial activity, revealing triacetylbalsaminol F (5) the highest antiplasmodial effects (IC(50) values: 0.4μM, 3D7; 0.2μM, Dd2). The highest antiplasmodial activity against the liver stages of P.berghei was also displayed by compound 5, with high inhibitory activity and no toxicity.
authors.affiliation: iMed.UL, Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
authors.forename: Cátia
authors.initials: C
authors.lastname: Ramalhete
authors.forename: Filipa P
authors.initials: FP
authors.lastname: da Cruz
authors.forename: Dinora
authors.initials: D
authors.lastname: Lopes
authors.forename: Silva
authors.initials: S
authors.lastname: Mulhovo
authors.forename: Virgílio E
authors.initials: VE
authors.lastname: Rosário
authors.forename: Miguel
authors.initials: M
authors.lastname: Prudêncio
authors.forename: Maria-José U
authors.initials: MJ
authors.lastname: Ferreira
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000469:parasitology*; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D029775:Momordica / Q000737:chemistry*; D010962:Plasmodium berghei / Q000187:drug effects*; D010963:Plasmodium falciparum / Q000187:drug effects*; D014315:Triterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D014315:Triterpenes