Tret'yakova Elena V, Ma Xinyuan, Kazakova Oxana B, Shtro Anna A, Petukhova Galina D, Klabukov Artem M, Dyatlov Danil S, Smirnova Anna A, Xu Huan, Xiao Sulong
Ufa Institute of Chemistry of the Ufa Federal Research Centre of the Russian Academy of Sciences, 71 Prospect Oktyabrya, 450054, Ufa, Russia.
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Phytochem Lett. 2022 Oct;51:91-96. doi: 10.1016/j.phytol.2022.07.010. Epub 2022 Aug 2.
A chemical library was constructed based on the resin acids (abietic, dehydroabietic, and 12-formylabietic) and its diene adducts (maleopimaric and quinopimaric acid derivatives). The one-pot three-component CuCl-catalyzed aminomethylation of the abietane diterpenoid propargyl derivatives was carried out by formaldehyde and secondary amines (diethylamine, pyrrolidine, morpholine, and homopiperazine). All compounds were tested for cytotoxicity and antiviral activity against influenza virus A/Puerto Rico/8/34 (H1N1) in MDCK cells and SARS-CoV-2 pseudovirus in BHK-21-hACE2 cells. Among 21 tested compounds, six derivatives demonstrated a selectivity index (SI) higher than 10, and their IC values ranged from 0.19 to 5.0 μM. Moreover, two derivatives exhibited potent anti-SARS-CoV-2 infection activity. The antiviral activity and toxicity strongly depended on the nature of the diterpene core and heterocyclic substituent. Compounds and bearing pyrrolidine moieties demonstrated the highest virus-inhibiting activity with SIs of 128.6 and 146.8, respectively, and appeared to be most effective when added at the time points 0-10 and 1-10 h of the viral life cycle. Molecular docking and dynamics modeling were adopted to investigate the binding mode of compound into the binding pocket of influenza A virus M2 protein. Compound with a pyrrolidine group at C20 of 17-formylabietic acid was a promising anti-SARS-CoV-2 agent with an EC of 10.97 µM and a good SI value > 18.2. Collectively, our data suggested the potency of diterpenic Mannich bases as effective anti-influenza and anti-COVID-19 compounds.
基于树脂酸（枞酸、去氢枞酸和12-甲酰基枞酸）及其二烯加合物（马来海松酸和奎诺酸衍生物）构建了一个化学文库。通过甲醛和仲胺（二乙胺、吡咯烷、吗啉和高哌嗪）进行了一锅三组分CuCl催化的枞烷二萜炔丙基衍生物的氨甲基化反应。对所有化合物进行了细胞毒性测试以及针对MDCK细胞中甲型流感病毒A/波多黎各/8/34（H1N1）和BHK-21-hACE2细胞中SARS-CoV-2假病毒的抗病毒活性测试。在21种测试化合物中，六种衍生物的选择性指数（SI）高于10，其IC值范围为0.19至5.0 μM。此外，两种衍生物表现出强效的抗SARS-CoV-2感染活性。抗病毒活性和毒性在很大程度上取决于二萜核心和杂环取代基的性质。带有吡咯烷部分的化合物 和 表现出最高的病毒抑制活性，SI分别为128.6和146.8，并且在病毒生命周期的0-10和1-10小时时间点添加时似乎最有效。采用分子对接和动力学建模来研究化合物 与甲型流感病毒M2蛋白结合口袋的结合模式。在17-甲酰基枞酸的C20处带有吡咯烷基团的化合物 是一种有前景的抗SARS-CoV-2药物，其EC为10.97 μM，SI值良好> 18.2。总体而言，我们的数据表明二萜曼尼希碱作为有效的抗流感和抗COVID-19化合物具有潜力。
