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

• Published in: Phytochemistry (Oxford) 2007-04, Vol.68 (8), p.1200-1205
• Main Authors: Pillay, Pamisha, Vleggaar, Robert, Maharaj, Vinesh J., Smith, Peter J., Lategan, Carmen A., Chouteau, Frank, Chibale, Kelly
• Format: Article
• Language: English
• Subjects: 2(5 H)-furanone; acetates; Animals; Antimalarials - chemistry; Antimalarials - isolation & purification; Antimalarials - pharmacology; Antiplasmodial activity; Asteraceae; Binding Sites; Biological and medical sciences; Chemical constitution; Chemical Fractionation; CHO Cells; Cricetinae; Cricetulus; cultured cells; Cytotoxicity; Fundamental and applied biological sciences. Psychology; Furans - chemistry; Furans - isolation & purification; Furans - pharmacology; General pharmacology; hamsters; hirsutinolide; Hirsutinolides; Medical sciences; Molecular Structure; Mucochloric and mucobromic acids; Nuclear Magnetic Resonance, Biomolecular; Pharmacognosy. Homeopathy. Health food; Pharmacology. Drug treatments; Pharmacophores; phytochemicals; Plant Extracts - chemistry; Plant Leaves - chemistry; Plant physiology and development; Plasmodium falciparum; Plasmodium falciparum - drug effects; Structure-Activity Relationship; structure-activity relationships; Vernonia; Vernonia - chemistry; Vernonia staehelinoides
• ISSN: 0031-9422; 1873-3700
• DOI: 10.1016/j.phytochem.2007.02.019

Bioassay-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(5 H)-furanone substructures. 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(5 H)-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 appropriate 2(5 H)-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(5 H)-furanone substructure is a key pharmacophore in the observed antiplasmodial activity.