College of Graduate Studies, Walailak University, Nakhon Si Thammarat, 80160, Thailand.
Research Center in Tropical Pathobiology, Walailak University, Nakhon Si Thammarat, 80160, Thailand.
BMC Complement Med Ther. 2024 Jul 25;24(1):282. doi: 10.1186/s12906-024-04580-5.
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.
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.
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 IC being 19.93 µM. Additionally, there was no toxicity towards Vero cells (CC = 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 LD value of 4,000 mg/kg, and importantly, non-hepatotoxic, non-carcinogenic, and non-cytotoxic effects.
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.
疟疾是一个重大的全球健康问题，特别是在热带和亚热带国家。随着对青蒿素一线治疗的耐药性不断增加，迫切需要发现新的抗疟药物。麻疯树，一种在传统医学中用于多种用途的植物，已被我们的研究小组研究其细胞毒性特性。本研究的目的是探讨从麻疯树中分离出的化合物在抗疟原虫活性、与疟原虫乳酸脱氢酶（PfLDH）的相互作用、寄生虫生存的关键酶、药代动力学和毒性特征方面的潜在应用。
使用寄生虫乳酸脱氢酶（pLDH）测定法，评估分离出的化合物对多药耐药株 P. falciparum K1 的体外抗疟原虫活性。使用 MTT（3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四唑溴化物）测定法测定对 Vero 细胞的体外细胞毒性。使用分子对接研究分离出的化合物与靶酶 PfLDH 的相互作用。此外，使用在线网络工具 SwissADME 和 ProTox-II 分别估计药代动力学和毒性特性。
从麻疯树根中分离出的 7 种化合物中，属于吡喃氧杂酮类的 rheediachromenoxanthone（5）表现出良好的体外抗疟原虫活性，IC 为 19.93 μM。此外，对 Vero 细胞没有毒性（CC = 112.34 μM），选择性指数（SI）为 5.64。分子对接分析表明，化合物（5）对 PfLDH 表现出很强的结合亲和力，为-8.6 kcal/mol，并通过与关键氨基酸残基如 ASP53、TYR85 和 GLU122 形成氢键而稳定。药代动力学预测表明，化合物（5）具有良好的类药性和所需的药代动力学特征。这些特征包括在胃肠道中有良好的吸收、被分类为非通透性糖蛋白（P-gp）的底物、不抑制 CYP2C19、易于合成、预测 LD 值为 4000 mg/kg 高、重要的是，无肝毒性、非致癌性和非细胞毒性作用。
本研究表明，从麻疯树中分离出的化合物对 P. falciparum 具有活性。Rheediachromenoxanthone 具有作为潜在的抗疟药物的重要潜力。
