Antimalarial potential of compounds isolated from Mammea siamensis T. Anders. flowers: in vitro and molecular docking studies

Abstract

Background: The emergence of antimalarial drug resistance encourages the search for new antimalarial agents. Mammea siamensis belongs to the Calophyllaceae family, which is a medicinal plant that is used in traditional Thai preparations. The hexane and dichloromethane extracts of this plant were found to have potent antimalarial activity. Therefore, this study aimed to isolate active compounds from M. siamensis flowers and evaluate their antimalarial potential and their interactions with Plasmodium falciparum lactate dehydrogenase (PfLDH).

Methods: The compounds from M. siamensis flowers were isolated by chromatographic techniques and evaluated for their antimalarial activity against chloroquine (CQ)-resistant P. falciparum (K1) strains using a parasite lactate dehydrogenase (pLDH) assay. Interactions between the isolated compounds and the PfLDH enzyme were investigated using a molecular docking method.

Results: The isolation produced the following thirteen compounds: two terpenoids, lupeol (1) and a mixture of β-sitosterol and stigmasterol (5); two mammea coumarins, mammea A/AA cyclo D (6) and mammea A/AA cyclo F (7); and nine xanthones, 4,5-dihydroxy-3-methoxyxanthone (2), 4-hydroxyxanthone (3), 1,7-dihydroxyxanthone (4), 1,6-dihydroxyxanthone (8), 1-hydroxy-5,6,7-trimethoxyxanthone (9), 3,4,5-trihydroxyxanthone (10), 5-hydroxy-1-methoxyxanthone (11), 2-hydroxyxanthone (12), and 1,5-dihydroxy-6-methoxyxanthone (13). Compound 9 exhibited the most potent antimalarial activity with an IC₅₀ value of 9.57 µM, followed by 10, 1, 2 and 13 with IC₅₀ values of 15.48, 18.78, 20.96 and 22.27 µM, respectively. The molecular docking results indicated that 9, which exhibited the most potent activity, also had the best binding affinity to the PfLDH enzyme in terms of its low binding energy (-7.35 kcal/mol) and formed interactions with ARG109, ASN140, and ARG171.

Conclusion: These findings revealed that isolated compounds from M. siamensis flowers exhibited antimalarial activity. The result suggests that 1-hydroxy-5,6,7-trimethoxyxanthone is a possible lead structure as a potent inhibitor of the PfLDH enzyme.

Keywords: Anti-malarial activity; Mammea siamensis; Molecular docking; Plasmodium falciparum; Xanthone.

Fig. 1

Structures of the compounds isolated from M. siamensis flowers

Fig. 2

Predicted binding modes and H-bond interactions of two active compounds, artesunate and chloroquine, with the PfLDH enzyme. The backbone of the PfLDH enzyme is presented in a blue ribbon model, and all hydrogen bonding residues are shown as stick models and labeled by heteroatoms. The compounds are labeled by heteroatoms as follows: yellow for C, white for H, cyan for N, red for O, and green for Cl. Green dashed lines represent hydrogen bond interactions and represent bond length in angstroms (Å). a: 1-Hydroxy-5,6,7-trimethoxyxanthone (9), b: 3,4,5-Trihydroxyxanthone (10), c: Artesunate, d: Chloroquine