Lupane-type pentacyclic triterpenes such as betulin and betulinic acid play an important role in the search for new therapies that would be effective in controlling viral infections. The aim of this study was the synthesis and evaluation of in vitro anti-HIV-1 activity for phosphate derivatives of 3-carboxyacylbetulin 3–5 as well as an in silico study of new compounds as potential ligands of the C-terminal domain of the HIV-1 capsid–spacer peptide 1 (CA-CTD-SP1) as a molecular target of HIV-1 maturation inhibitors. In vitro studies showed that 28-diethoxyphosphoryl-3-O-(3′,3′-dimethylsuccinyl)betulin (compound 3), the phosphate analog of bevirimat (betulinic acid derivative, HIV-1 maturation inhibitor), has IC₅₀ (half maximal inhibitory concentration) equal to 0.02 μM. Compound 3 inhibits viral replication at a level comparable to bevirimat and is also more selective (selectivity indices = 1250 and 967, respectively). Molecular docking was used to examine the probable interaction between the phosphate derivatives of 3-carboxyacylbetulin and C-terminal domain (CTD) of the HIV-1 capsid (CA)–spacer peptide 1 (SP1) fragment of Gag protein, designated as CTD-SP1. Compared with interactions between bevirimat (BVM) and the protein, an increased number of strong interactions between ligand 3 and the protein, generated by the phosphate group, were observed. These compounds might have the potential to also inhibit SARS-CoV2 proteins, in as far as the intrinsically imprecise docking scores suggest.

中文翻译：

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3-羧基桦木醇的磷酸衍生物：合成、体外抗 HIV 和分子对接研究。

羽扇豆烷型五环三萜类化合物，例如桦木醇和桦木酸，在寻找有效控制病毒感染的新疗法中发挥着重要作用。本研究的目的是合成和评估 3-羧酰基桦木醇3 – 5磷酸酯衍生物的体外抗 HIV-1 活性，以及​​对新化合物作为 3-羧基桦木醇 C 端结构域的潜在配体进行计算机研究。 HIV-1 衣壳间隔肽 1 (CA-CTD-SP1) 作为 HIV-1 成熟抑制剂的分子靶点。体外研究表明，28-二乙氧基磷酰基-3- O- (3',3'-二甲基琥珀酰基)桦木醇（化合物3）是贝维马特（桦木酸衍生物，HIV-1 成熟抑制剂）的磷酸盐类似物，具有 IC ₅₀（半数）最大抑制浓度）等于0.02 μM。化合物3抑制病毒复制的水平与贝维马特相当，并且选择性也更高（选择性指数分别为 1250 和 967）。使用分子对接来检查 3-羧酰基桦木醇的磷酸盐衍生物与 HIV-1 衣壳 (CA) 的 C 末端结构域 (CTD) – Gag 蛋白的间隔肽 1 (SP1) 片段之间可能的相互作用，称为 CTD- SP1。与贝维里马 ( BVM ) 和蛋白质之间的相互作用相比，观察到配体3和蛋白质之间由磷酸基团产生的强相互作用数量增加。就本质上不精确的对接分数而言，这些化合物也可能具有抑制 SARS-CoV2 蛋白的潜力。