Antiplasmodial hirsutinolides from Vernonia staehelinoides and their utilization towards a simplified pharmacophore

Abstract

The dichloromethane extract of the leaves of Vernonia staehelinoides Harv. (Asteraceae) showed in vitro activity (IC 50 3 μg/ml) against the chloroquine-sensitive (D10) and the chloroquine-resistant (K1) strains of Plasmodium falciparum. Through conventional chromatographic techniques and bioassay-guided fractionation two structurally-related hirsutinolides displaying in vitro antiplasmodial activity (IC 50 0.2 μg/ml against D10) were isolated and identified by spectroscopic data. Compounds 1, 8α-(2-methylacryloyloxy)-3-oxo-1-desoxy-1,2-dehydrohirsutinolide-13-O-acetate, and 2, 8α-(5′-acetoxysenecioyloxy)-3-oxo-1-desoxy-1,2-dehydrohirsutinolide-13-O-acetate were found to be cytotoxic to mammalian Chinese Hamster Ovarian (CHO) cells at similar concentrations but proved to be attractive scaffolds for structure-activity relationship studies. Two main privileged substructures, a 2(5H)-furanone unit and a dihydrofuran-4-one unit, were identified as potential pharmacophores which may be responsible for the observed biological activity. Mucochloric and mucobromic acids were selected as openUP (July 2007) appropriate 2(5H)-furanone substructures and these were shown to have comparable activity against the D10 and superior activity against the K1 strains relative to the hirsutinolide natural product. Mucochloric and mucobromic acids also show selective cytotoxicity to the malaria parasites compared to mammalian (CHO) cells in vitro. The antiplasmodial data obtained in respect of these two acids suggests that the 2(5H)-furanone substructure is a key pharmacophore in the observed antiplasmodial activity. Graphical abstractBioassay-guided fractionation of the dichloromethane extract of the leaves of Vernonia staehelinoides led to the isolation of two structurally-related hirsutinolides, displaying in vitro antiplasmodial activity. The compounds lacked selectivity (cytotoxicity vs. bioactivity) but the results led to the identification of mucochloric and mucobromic acids as privileged 2(5H)-furanone substructures.

Óleos essenciais das folhas de Vernonia Remotiflora e Vernonia Brasiliana: composição química e atividade biológica

“…3 Inúmeras espécies de Vernonia integram o elenco de plantas medicinais de várias partes do mundo, inclusive do Brasil, onde o uso de plantas como fonte de medicamentos é bastante difundido. Compostos bioativos como lactonas sesquiterpênicas com propriedades anticâncer e antiplasmódica, 4,5 glicosídeos esteroidais com atividade anti-inflamatória 6 e sesquiterpenoides citotóxicos 7 têm sido isolados de plantas do gênero Vernonia. Adicionalmente, plantas deste gênero são ricas em glândulas oleíferas e muitos dos seus óleos essenciais apresentam atividades biológicas, como antimicrobiana e inseticida.…”

The bioactivity of novel furanoterpenoids isolated from Siphonochilus aethiopicus

“…It is possible that the antiplasmodial activity of these compounds can be attributed to the furan moiety in the structure. Recently, two privileged substructures, a 2(5H)-furanone and a dihydrofuran-4-one moiety were identified as the possible chemical entities responsible for antiplasmodial activity of hirsutinolides isolated from Vernonia staehelinoides (Pillay et al, 2007). The mechanism of action of this class of antiplasmodial compounds is not known.…”

In vitro antiplasmodial activity of Withania frutescens —Solanaceae

“…Our previous study has shown that the dichloromethane fraction of W. frutescens leaves exhibited cytotoxic activity against cancer cell lines (Hep G2), which can be ascribed to the phytochemical constituents; the withanolides [7]. Earlier studies reported the antiplasmodial activity of some other sesquiterpenoid lactones, but in both reports high cytotoxicity was also associated with the compounds [22,23].…”