Antiplasmodial potential of isolated xanthones from Mesua ferrea Linn. roots: an in vitro and in silico molecular docking and pharmacokinetics study

Abstract

Background: Malaria is a major global health concern, particularly in tropical and subtropical countries. With growing resistance to first-line treatment with artemisinin, there is an urgent need to discover novel antimalarial drugs. Mesua ferrea Linn., a plant used in traditional medicine for various purposes, has previously been investigated by our research group for its cytotoxic properties. The objective of this study was to explore the compounds isolated from M. ferrea with regards to their potential antiplasmodial activity, their interaction with Plasmodium falciparum lactate dehydrogenase (PfLDH), a crucial enzyme for parasite survival, and their pharmacokinetic and toxicity profiles.

Methods: The isolated compounds were assessed for in vitro antiplasmodial activity against a multidrug-resistant strain of P. falciparum K1 using a parasite lactate dehydrogenase (pLDH) assay. In vitro cytotoxicity against Vero cells was determined using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. The interactions between the isolated compounds and the target enzyme PfLDH were investigated using molecular docking. Additionally, pharmacokinetic and toxicity properties were estimated using online web tools SwissADME and ProTox-II, respectively.

Results: Among the seven compounds isolated from M. ferrea roots, rheediachromenoxanthone (5), which belongs to the pyranoxanthone class, demonstrated good in vitro antiplasmodial activity, with the IC₅₀ being 19.93 µM. Additionally, there was no toxicity towards Vero cells (CC₅₀ = 112.34 µM) and a selectivity index (SI) of 5.64. Molecular docking analysis revealed that compound (5) exhibited a strong binding affinity of - 8.6 kcal/mol towards PfLDH and was stabilized by forming hydrogen bonds with key amino acid residues, including ASP53, TYR85, and GLU122. Pharmacokinetic predictions indicated that compound (5) possessed favorable drug-like properties and desired pharmacokinetic characteristics. These include high absorption in the gastrointestinal tract, classification as a non-substrate of permeability glycoprotein (P-gp), non-inhibition of CYP2C19, ease of synthesis, a high predicted LD₅₀ value of 4,000 mg/kg, and importantly, non-hepatotoxic, non-carcinogenic, and non-cytotoxic effects.

Conclusions: This study demonstrated that compounds isolated from M. ferrea exhibit activity against P. falciparum. Rheediachromenoxanthone has significant potential as a scaffold for the development of potent antimalarial drugs.

Keywords: Mesua ferrea Linn.; Plasmodium falciparum; Antiplasmodial activity; In silico pharmacokinetics; Molecular docking; Xanthones.

Fig. 1

Chemical structure of compounds 1–7 isolated from M. ferrea L. roots

Fig. 2

Predicted best binding mode of compounds within the active site of PfLDH. The PfLDH enzyme structure is represented as a light blue cartoon, and the interacting residues as ball and stick models, each labeled with its respective heteroatoms. The compounds are represented as ball and stick models and labeled according to their heteroatom elements: orange for carbon (C), white for hydrogen (H), red for oxygen (O), blue for nitrogen (N), and green for chlorine (Cl). Yellow dashed lines represent hydrogen bonds formed between interacting residues and compounds, with the associated bond length specified in angstroms (Å). Gray dashed lines represent hydrophobic interactions between interacting amino acid residues and the compounds. The compound, rheediachromenoxanthone (a), chloroquine (b), and artesunate (c)

Fig. 3

Superimposition of the best docked poses of rheediachromenoxanthone (orange), chloroquine (cyan), artesunate (magenta), and NADH (green) interacting with amino acid residues within the active site of PfLDH. The yellow dashed lines represent the hydrogen bonds

Fig. 4

Bioavailability radar plot for rheediachromenoxanthone (a), chloroquine (b), and artesunate (c). The pink area represents the optimal range for six physicochemical properties associated with oral bioavailability, and the red line represents the specific properties of each compound

Fig. 5

BOILED-Egg predictive model shows the placement of rheediachromenoxanthone, chloroquine, and artesunate. This model is conceptually grounded in two essential physicochemical properties: the WLOGP value, which reflects lipophilicity, and the TPSA value, which reflects polarity. The compound falling within the white region (albumin) represents a high probability of HIA absorption, while the compound falling within the yellow region (yolk) represents a high probability of BBB permeation. The compound falling within the gray region is unlikely to be absorbed through HIA or the BBB. The red dots represent the compound as the P-gp non-substrate (PGP-).