Naturally Occurring 8ß,13ß-kaur-15-en-17-al and Anti-Malarial Activity from Podocarpus polystachyus Leaves

Abstract

Despite much interest and studies toward the genus <i>Podocarpus</i>, the anti-malarial evaluation of <i>Podocarpus polystachyus</i>'s phytoconstituents remains lacking. Herein, the phytoconstituents of <i>P. polystachyus</i> leaves and their anti-malarial effect against <i>Plasmodium falciparum</i> were investigated for the first time. One new natural product, 8ß,13ß-kaur-15-en-17-al (<b>1</b>), along with three known compounds, 8ß,13ß-kaur-15-en-17-ol (<b>2</b>) and 13ß-kaur-16-ene (<b>3</b>), and α-tocopherol hydroquinone (<b>4</b>) were isolated via HR-ESI-MS and NMR analyses. Compounds <b>1</b> and <b>2</b> inhibited <i>P. falciparum</i> growth at 12 and 52 µM of IC₅₀, respectively. Their anti-malarial activity was associated with the in silico <i>P. falciparum</i> lactate dehydrogenase (<i>Pf</i>LDH) inhibition. Molecular docking of ligands <b>1</b> and <b>2</b> with the putative target <i>Pf</i>LDH revealed ~-2 kcal/mol of binding energies more negative than the control. Molecular dynamic simulations (100 ns) showed equal or smaller deviation values (RMSD, RMSF, Rg) and stronger interactions of <i>Pf</i>LDH-<b>1</b> and <i>Pf</i>LDH-<b>2</b> complexes via at least one consistent H-bond than the control. Additionally, a slightly increased <i>Pf</i>LDH H-bond profile in their interactions improved the <i>Pf</i>LDH dynamic and structural stabilities. Overall, this study supports the relevance of <b>1</b> and <b>2</b> as plasmodial growth inhibitors with their putative anti-<i>Pf</i>LDH activity, which could be a potential scaffold for developing anti-malarial drugs.