Design and Synthesis of Novel Dihydroxyindole-2-Carboxylic Acids as HIV-1 Integrase Inhibitors
Design and Synthesis of Novel Dihydroxyindole-2-Carboxylic Acids as HIV-1 Integrase Inhibitors
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DOI：
10.1177/095632020401500203
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发表时间：
2004-04
影响因子：
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通讯作者：
M. Sechi;Gianfranco Angotzi;R. Dallocchio;A. Dessì;F. Carta;L. Sannia;A. Mariani;S. Fiori;
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文献类型：
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作者：
M. Sechi;Gianfranco Angotzi;R. Dallocchio;A. Dessì;F. Carta;L. Sannia;A. Mariani;S. Fiori;
在寻找新的HIV-1整合酶（IN）抑制剂的过程中，我们合成并评估了5,6-二羟基吲哚-2-羧酸（DHICA）及其一系列衍生物的生物活性。这些化合物被设计为咖啡酸苯乙酯 (CAPE) 丙烯酸酯部分的构象受限类似物。 DHICA 是黑色素生物合成的中间体，通过新颖的合成路线制备为单体单元。为了进行连贯的 SAR 研究，合成了两个系列的 DHICA 酰胺。首先，为了验证先前确定的基于 CAPE 的三点药效团在抑制剂设计中的实用性，我们制备了一系列缺乏和含有羟基的苄基或苯乙胺取代的衍生物。其次，还制备了含有各种氨基烷基胺接头的 DHICA 二聚体，目的是提高效力。所有化合物均在基于酶的测定中针对纯化的 IN 和 C65S 突变体进行了测试。还测试了它们在卵巢癌细胞系中的细胞毒性以及在 HIV-1 感染的 CEM 细胞中的抗病毒活性。七种化合物抑制纯化 IN 的催化活性，IC50 值低于 10 μM。进行了进一步的计算对接研究以确定标题化合物与 IN 活性位点的相互作用模式。残基 K156、K159 和 D64 对于抗纯化 IN 的效力最重要。
In a search for new HIV-1 integrase (IN) inhibitors, we synthesized and evaluated the biological activity of 5,6-dihydroxyindole-2-carboxylic acid (DHICA) and a series of its derivatives. These compounds were designed as conformationally constrained analogues of the acrylate moiety of caffeic acid phenethyl ester (CAPE). DHICA, an intermediate in the biosynthesis of melanins, was prepared as a monomeric unit by a novel synthetic route. In order to perform coherent SAR studies, two series of DHICA amides were synthesized. First, to validate the utility of a previously identified three-point pharmacophore based on CAPE in inhibitor design, we prepared a series of benzyl- or phenylethylamine substituted derivatives lacking and containing hydroxyl groups. Second, dimers of DHICA containing various aminoalkylamine linkers were also prepared with a goal to increase potency. All compounds were tested against purified IN and the C65S mutant in enzyme-based assays. They were also tested for cytotoxicity in an ovarian carcinoma cell line and antiviral activity in HIV-1-infected CEM cells. Seven compounds inhibited catalytic activities of purified IN with IC50 values below 10 μM. Further computational docking studies were performed to determine the title compounds' mode of interaction with the IN active site. The residues K156, K159 and D64 were the most important for potency against purified IN.