The 4-aryl-2-hydroxy-4-oxo-2-butenoic acids and their isosteric tetrazoles are among an emerging class of aryl beta-diketo (ADK)-based agents which exhibit potent inhibition of HIV-1 integrase (IN)-catalyzed strand transfer (ST) processes, while having much reduced potencies against 3'-processing (3'-P) reactions. In the current study, L-708,906 (10e) and 5CITEP (13b), which are two examples of ADK inhibitors that have been reported by Merck and Shionogi pharmaceutical companies, served as model ADK leads. Structural variations to both the "left" and "right" sides of these molecules were made in order to examine effects on HIV-1 integrase inhibitory potencies. It was found that a variety of groups could be introduced onto the left side aryl ring with maintenance of good ST inhibitory potency. However, introduction of carboxylic acid-containing substituents onto the left side aryl ring enhanced 3'-P inhibitory potency and reduced selectivity toward ST reactions. Although both L-708,906 and 5CITEP show potent inhibition of IN in biochemical assays, there is a disparity of antiviral activity in cellular assays using HIV-1-infected cells. Neither 5CITEP nor any other of the indolyl-containing inhibitors exhibit significant antiviral effects in cellular systems. Alternatively, consistent with literature reports, L-708,906 does provide antiviral protection at low micromolar concentrations. Interestingly, several analogues of L-708,906 with varied substituents on the left side aryl ring, while having good inhibitory potencies against IN in extracellular assays, are not antiviral in whole-cell systems.

中文翻译：

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含有3-芳基-1,3-二酮的化合物作为HIV-1整合酶抑制剂的结构活性。

4-芳基-2-羟基-4-氧代-2-丁烯酸及其等排四唑是新兴的一类基于芳基β-二酮（ADK）的药物，可有效抑制HIV-1整合酶（IN）-催化链转移（ST）过程，同时对3'-加工（3'-P）反应的效力大大降低。在当前的研究中，默克制药和盐野吉制药公司已报道的ADK抑制剂的两个实例L-708,906（10e）和5CITEP（13b）作为模型ADK的线索。为了检查对HIV-1整合酶抑制能力的影响，对这些分子的“左侧”和“右侧”均进行了结构变化。发现可以在保持良好的ST抑制效力的情况下将各种基团引入到左侧芳基环上。然而，在左侧芳基环上引入含羧酸的取代基可增强3'-P抑制能力，并降低对ST反应的选择性。尽管L-708,906和5CITEP在生化测定中均显示出对IN的有效抑制作用，但在使用HIV-1感染细胞的细胞测定中，抗病毒活性存在差异。5CITEP或任何其他吲哚基抑制剂均未在细胞系统中表现出显着的抗病毒作用。或者，与文献报道一致，L-708,906确实在低微摩尔浓度下提供了抗病毒保护。有趣的是，在左侧芳基环上具有不同取代基的L-708,906的几种类似物，尽管在细胞外测定中对IN具有良好的抑制能力，但在全细胞系统中却不是抗病毒药。