In response to the urgent need to control Coronavirus disease 19 (COVID-19), this study aims to explore potential anti-SARS-CoV-2 agents from natural sources. Moreover, cytokine immunological responses to the viral infection could lead to acute respiratory distress which is considered a critical and life-threatening complication associated with the infection. Therefore, the anti-viral and anti-inflammatory agents can be key to the management of patients with COVID-19. Four bioactive compounds, namely ferulic acid 1, rutin 2, gallic acid 3, and chlorogenic acid 4 were isolated from the leaves of Pimenta dioica (L.) Merr (ethyl acetate extract) and identified using spectroscopic evidence. Furthermore, molecular docking and dynamics simulations were performed for the isolated and identified compounds (1–4) against SARS-CoV-2 main protease (Mpro) as a proposed mechanism of action. Furthermore, all compounds were tested for their half-maximal cytotoxicity (CC₅₀) and SARS-CoV-2 inhibitory concentrations (IC₅₀). Additionally, lung toxicity was induced in rats by mercuric chloride and the effects of treatment with P. dioca aqueous extract, ferulic acid 1, rutin 2, gallic acid 3, and chlorogenic acid 4 were recorded through measuring TNF-α, IL-1β, IL-2, IL-10, G-CSF, and genetic expression of miRNA 21-3P and miRNA-155 levels to assess their anti-inflammatory effects essential for COVID-19 patients. Interestingly, rutin 2, gallic acid 3, and chlorogenic acid 4 showed remarkable anti-SARS-CoV-2 activities with IC₅₀ values of 31 µg/mL, 108 μg/mL, and 360 µg/mL, respectively. Moreover, the anti-inflammatory effects were found to be better in ferulic acid 1 and rutin 2 treatments. Our results could be promising for more advanced preclinical and clinical studies especially on rutin 2 either alone or in combination with other isolates for COVID-19 management.

中文翻译：

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Pimenta dioica (L.) Merr。生物活性成分发挥抗 SARS-CoV-2 和抗炎活性：分子对接和动力学、体外和体内研究


为了满足控制冠状病毒病 19 (COVID-19) 的迫切需要，本研究旨在从天然来源中探索潜在的抗 SARS-CoV-2 药物。此外，细胞因子对病毒感染的免疫反应可能导致急性呼吸窘迫，这被认为是与感染相关的严重且危及生命的并发症。因此，抗病毒和抗炎药物可能是治疗 COVID-19 患者的关键。从Pimenta dioica (L.) Merr（乙酸乙酯提取物）的叶子中分离出四种生物活性化合物，即阿魏酸1 、芦丁2 、没食子酸3和绿原酸4 ，并使用光谱证据进行鉴定。此外，对分离和鉴定的针对 SARS-CoV-2 主要蛋白酶 (Mpro) 的化合物 ( 1-4 ) 进行了分子对接和动力学模拟，作为拟议的作用机制。此外，还测试了所有化合物的半最大细胞毒性 (CC ₅₀ ) 和 SARS-CoV-2 抑制浓度 (IC ₅₀ )。此外，氯化汞诱导大鼠肺毒性，并通过测量TNF-α、IL- 1β 、 IL-2、IL-10、G-CSF 以及 miRNA 21-3P 和 miRNA-155 水平的基因表达，以评估它们对 COVID-19 患者至关重要的抗炎作用。 有趣的是，芦丁2 、没食子酸3和绿原酸4显示出显着的抗 SARS-CoV-2 活性，IC ₅₀值分别为 31 µg/mL、108 µg/mL 和 360 µg/mL。此外，发现阿魏酸1和芦丁2治疗的抗炎作用更好。我们的结果有望用于更先进的临床前和临床研究，尤其是单独使用芦丁2或与其他分离株联合用于 COVID-19 管理的研究。