Since the beginning of the human immunodeficiency virus (HIV) epidemic, many groups of drugs characterized by diverse mechanisms of action have been developed, which can suppress HIV viremia. 3-O-(3′,3′-Dimethylsuccinyl) betulinic acid, known as bevirimat (BVM), was the first compound in the class of HIV maturation inhibitors. In the present work, phosphate and phosphonate derivatives of 3-carboxyacylbetulinic acid were synthesized and evaluated for anti-HIV-1 activity. In vitro studies showed that 30-diethylphosphonate analog of BVM (compound 14a) has comparable effects to BVM (half maximal inhibitory concentrations (IC50) equal to 0.02 μM and 0.03 μM, respectively) and is also more selective (selectivity indices: 3450 and 967, respectively). To investigate the possible mechanism of antiviral effect of 14a, molecular docking was carried out on the C-terminal domain (CTD) of HIV-1 capsid (CA)–spacer peptide 1 (SP1) fragment of Gag protein, designated as CTD-SP1, which was described as a molecular target for maturation inhibitors. Compared with interactions between BVM and the protein, an increased number of strong interactions between ligand 14a and protein, generated by the phosphonate group, was observed.

中文翻译：

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Bevirimat的新型磷类似物：抗HIV-1活性的合成，评价和分子对接研究

自人类免疫缺陷病毒（HIV）流行开始以来，已开发出许多具有多种作用机制的药物，它们可以抑制HIV病毒血症。3-O-（3'，3'-二甲基琥珀酰基）桦木酸，被称为bevirimat（BVM），是HIV成熟抑制剂中的第一种化合物。在目前的工作中，合成了3-羧基酰基白果酸的磷酸酯和膦酸酯衍生物，并评估了其抗HIV-1活性。体外研究表明，BVM的30-二乙基膦酸酯类似物（化合物14a）具有与BVM相当的作用（半数最大抑制浓度（IC50）分别等于0.02μM和0.03μM），并且具有更高的选择性（选择性指数：3450和967） ， 分别）。为了研究14a抗病毒作用的可能机制，对Gag蛋白的HIV-1衣壳（CA）–间隔肽1（SP1）片段的C端结构域（CTD）进行了分子对接，命名为CTD-SP1，被描述为成熟抑制剂的分子靶标。与BVM和蛋白质之间的相互作用相比，观察到由膦酸酯基团产生的配体14a与蛋白质之间的强相互作用增加了。