Antiplasmodial activity of coumarins isolated from <i>Polygala boliviensis</i> : <i>in vitro</i> and <i>in silico</i> studies

Abstract

<i>Polygala boliviensis</i> is found in the Brazilian semiarid region. This specie is little chemically and biologically studied. <i>Polygala</i> spp. have different metabolites, especially coumarins. Studies indicate that coumarins have antimalarial potential, denoting the importance of researching new active compounds from plants, since the resistance of <i>Plasmodium</i> strains to conventional therapy has increased. The present study aimed to evaluate the antiplasmodial activity of auraptene and poligalen against a chloroquine-resistant strain of <i>Plasmodium falciparum</i>. Coumarins were isolated from <i>P. boliviensis</i> by open column chromatography and identified by Nuclear Magnetic Resonance Spectroscopy. A cytotoxicity assay was carried out using MTT test, and the <i>in vitro</i> antiplasmodial activity was evaluated using the W2 strain. The antiplasmodial activity results found were IC₅₀=0.171 ± 0.016 for auraptene and 0.164 ± 0.012 for poligalen; the selectivity indexes were 78.71 and 609.76, respectively. Inverse virtual screening in the BRAMMT database by OCTOPUS 1.2 was applied to coumarins to find potential <i>P. falciparum</i> targets and showed higher affinity energy of auraptene for purine nucleoside phosphorylase (PfPNP) and of poligalen for dihydroorotate dehydrogenase (PfDHODH). Molecular Dynamics studies (MD and MM-GBSA) approach were applied to calculate binding energies against selected <i>P. falciparum</i> targets and showed that all coumarins were stable at the binding site during simulations. Furthermore, energies were favorable for complexation. This is the first report of auraptene in <i>P. boliviensis</i> species and of <i>in vitro</i> antiplasmodial activity of auraptene and poligalen. <i>In silico</i> studies indicated that the mechanism of action of coumarins is the inhibition of PfPNP and PfDHODH.Communicated by Ramaswamy H. Sarma.