Antiplasmodial activity of coumarins isolated from Polygala boliviensis: in vitro and in silico studies

Abstract

Polygala boliviensis is found in the Brazilian semiarid region. This specie is little chemically and biologically studied. Polygala 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 Plasmodium 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 Plasmodium falciparum. Coumarins were isolated from P. boliviensis by open column chromatography and identified by Nuclear Magnetic Resonance Spectroscopy. A cytotoxicity assay was carried out using MTT test, and the in vitro 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 P. falciparum 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 P. falciparum 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 P. boliviensis species and of in vitro antiplasmodial activity of auraptene and poligalen. In silico studies indicated that the mechanism of action of coumarins is the inhibition of PfPNP and PfDHODH.

Communicated by Ramaswamy H. Sarma

Keywords:

• Dihydroorotate dehydrogenase
• malaria
• Plasmodium falciparum
• purine nucleoside phosphorylase

Acknowledgments

The authors thank Alex Gutterres Taranto and Eduardo Habib Bechelane Maia for providing the software OCTOPUS 1.2, and Jonathan Doyle and Mark O'Reilly (English Native Speakers) for checking the English of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The authors acknowledge the financial support provided by CAPES (Financial Code 001/Portaria n° 206/2018), Fapemig APQ Universal 00557-14, 02742-17 and FAPESB (Grant ID: BOL 0710/2016).