Instituto Multidisciplinario de Investigación y Transferencia Agroalimentaria y Biotecnológica (IMITAB), Instituto Académico Pedagógico de Ciencias Básicas y Aplicadas, Universidad Nacional de Villa María, Córdoba, Argentina.
Programa de Estudio y Control de Enfermedades Tropicales-PECET, Universidad de Antioquia, Medellín, Colombia.
BMC Complement Med Ther. 2022 Jun 13;22(1):156. doi: 10.1186/s12906-022-03636-8.
Despite the number of deaths and the significant economic and social costs associated with Chagas, Leishmaniasis and Malaria diseases worldwide, available drugs are limited and have serious side effects and high toxicity for the patient. Therefore, there is an urgent need for safe, low-cost, and effective treatments. Natural products are an important source of bioactive compounds and there is current interest in finding natural bioactive molecules that can be used for treating these parasitic diseases. In the present study we proposed to evaluate the in vitro antiparasitic activity of new menthol derivatives against Trypanosoma cruzi, Leishmania braziliensis and Plasmodium falciparum; moreover, we propose to explore their mode of action through in silico approaches.
A series of carbonate prodrugs (1-9) were synthesized from menthol with different aliphatic alcohols. Spectroscopic techniques were used to confirm the structures of the synthesized compounds. The cytotoxicity of the compounds was assessed using U-937 cells. In vitro trypanocidal, leishmanicidal and antiplasmodial activity were evaluated using a T. cruzi, L. braziliensis and P. falciparum organism, respectively. In addition, in silico studies were also performed through molecular dynamics simulations and MM-PBSA analysis.
The assay revealed that most of the compounds were highly active against intracellular amastigotes of T. cruzi and L. braziliensis, and had moderate activity against the total forms of P. falciparum. Compound 2 was one of the drugs that showed a high selectivity index (SI) for the three organisms evaluated. The prediction of the ADME properties suggests that all the compounds have drug-like molecular properties and the probability to be lead candidates. Finally, molecular dynamics simulations, and MM-PBSA studies indicate that menthol at the substrate binding site of TcDHODH, LbDHODH and PfDHODH is structurally stable in the same order as the natural substrate; also, interactions of menthol with residues involved in the inhibition of TcDHODH and PfDHODH proteins were predicted.
The present study demonstrates that menthol prodrugs are promising antiparasitic agents; however, the mechanisms of action proposed in this study need to be experimentally verified by future enzymatic assays.
尽管全球范围内的死亡人数以及与恰加斯病、利什曼病和疟疾相关的巨大经济和社会成本，但现有的药物数量有限，且对患者具有严重的副作用和高毒性。因此，迫切需要安全、低成本且有效的治疗方法。天然产物是生物活性化合物的重要来源，目前人们有兴趣寻找可用于治疗这些寄生虫病的天然生物活性分子。在本研究中，我们提出评估新薄荷醇衍生物对克氏锥虫、巴西利什曼原虫和恶性疟原虫的体外抗寄生虫活性；此外，我们还通过计算方法提出探索其作用模式。
用不同的脂肪醇合成了一系列碳酸酯前药（1-9）。采用光谱技术确认了所合成化合物的结构。用 U-937 细胞评估化合物的细胞毒性。采用克氏锥虫、巴西利什曼原虫和恶性疟原虫分别评估化合物的体外杀锥虫、杀利什曼原虫和抗疟原虫活性。此外，还通过分子动力学模拟和 MM-PBSA 分析进行了计算研究。
该测定结果表明，大多数化合物对克氏锥虫和巴西利什曼原虫的细胞内无鞭毛体具有高度活性，对全形态恶性疟原虫也具有中等活性。化合物 2 是对三种评估的生物均显示高选择性指数（SI）的药物之一。ADME 性质的预测表明，所有化合物都具有类药性的分子性质，且有成为先导候选物的可能性。最后，分子动力学模拟和 MM-PBSA 研究表明，薄荷醇在 TcDHODH、LbDHODH 和 PfDHODH 的底物结合位点结构稳定，与天然底物的顺序相同；此外，还预测了薄荷醇与参与抑制 TcDHODH 和 PfDHODH 蛋白的残基的相互作用。
本研究表明，薄荷醇前药是有前途的抗寄生虫药物；然而，本研究提出的作用机制需要通过未来的酶促测定实验来验证。
