γ-Lactones from Persea americana and Persea fulva – in Vitro and in Silico Evaluation of Trypanosoma cruzi Activity,Chemistry & Biodiversity

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γ-Lactones from Persea americana and Persea fulva – in Vitro and in Silico Evaluation of Trypanosoma cruzi Activity
Chemistry & Biodiversity ( IF 2.3 ) Pub Date : 2021-07-12 , DOI: 10.1002/cbdv.202100362
Isabella Mary A Reis ₁ , Eric Umehara ₂ , Rodrigo S Conceição ₁ , Larissa de M Oliveira ₁ , Manoelito Coelho Dos S Junior ₁ , Thais A Costa-Silva ₂ , Maiara Amaral ₃ , Andre G Tempone ₃ , Alexsandro Branco ₁ , João Henrique G Lago ₂

Affiliation

In the present study, five known γ-lactones (majoranolide B – 1, majorenolide – 2, majorynolide – 3, lincomolide D – 4, and isolinderanolide E – 5), as well as a new one (perseanolide – 6), were isolated from Persea fulva and P. americana. All isolated compounds exhibited potential activity against trypomastigote forms of Trypanosoma cruzi, whereas compounds 2 (EC₅₀ of 4.8 μM) and 6 (EC₅₀ of 3.6 μM) displayed superior activity than the positive control benznidazole (EC₅₀ of 16.4 μM), with selectivity index (SI) values of 17.8 and >55.6, respectively (benznidazole, SI>12.2). Molecular docking studies were performed for 1–6 against six T. cruzi molecular targets. Using this approach, we observed that, even though perseanolide (6) showed favorable docking to several studied targets, the results were especially promising for hypoxanthine phosphoribosyl transferase (PDB 1TC1). As PDB 1TC1 is associated to the transference of a monophosphorylated ribose from phosphoribosylpyrophosphate (PRPP) in the ribonucleotide synthesis pathway, this interaction may affect the survival of T. cruzi in mammalian cells. The data herein also indicate that possible intermolecular interactions between 6 and PDB 1TC1 derive from (i) hydrogen bonds in the α,β-unsaturated-γ-lactone unity and (ii) hydrophobic interactions in the long-chain alkyl group. Based on our results, perseanolide (6), reported for the first time in this work, can auspiciously contribute to future works regarding new trypanocidal agents.

中文翻译：

来自 Persea americana 和 Persea fulva 的 γ-内酯 - 克氏锥虫活性的体外和计算机评估

在本研究中，分离出了五种已知的γ-内酯（majoranolide B – 1、majorenolide – 2、majorynolide – 3、lincomolide D – 4和isolinderanolide E – 5）以及一种新的γ-内酯（perseanolide – 6）来自Persea fulva和P. americana。所有分离的化合物都表现出对抗克氏锥虫的潜在活性，而化合物2（EC ₅₀为 4.8 μM）和化合物 6（EC ₅₀为 3.6 μM）显示出比阳性对照苯并硝唑（EC ₅₀16.4 μM)，选择性指数 (SI) 值分别为 17.8 和 >55.6（苯并硝唑，SI>12.2）。为进行分子对接研究1 - 6对六种克氏锥虫的分子靶点。使用这种方法，我们观察到，尽管豆内酯 ( 6 ) 显示出与几个研究目标的良好对接，但次黄嘌呤磷酸核糖转移酶 (PDB 1TC1) 的结果特别有希望。由于 PDB 1TC1 与核糖核苷酸合成途径中来自磷酸核糖焦磷酸 (PRPP) 的单磷酸化核糖的转移有关，因此这种相互作用可能会影响T. cruzi的存活在哺乳动物细胞中。本文的数据还表明6和 PDB 1TC1之间可能的分子间相互作用源自 (i) α,β-不饱和-γ-内酯单元中的氢键和 (ii) 长链烷基中的疏水相互作用。根据我们的研究结果，在这项工作中首次报道的perseanolide ( 6 ) 可以为未来关于新的锥虫杀灭剂的工作做出积极贡献。

更新日期：2021-09-13

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