1-Hydroxypyrido[2,3-d]pyrimidin-2(1H)-ones as novel selective HIV integrase inhibitors obtained via privileged substructure-based compound libraries
1-Hydroxypyrido[2,3-d]pyrimidin-2(1H)-ones as novel selective HIV integrase inhibitors obtained via privileged substructure-based compound libraries
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1-羟基吡啶并[2,3-d]嘧啶-2(1H)-酮作为新型选择性 HIV 整合酶抑制剂，通过基于特权子结构的化合物库获得
DOI：
10.1016/j.bmc.2017.09.006
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发表时间：
2017-10-15
影响因子：
3.5
通讯作者：
Liu, Xinyong
中科院分区：
文献类型：
--
作者：
Gao, Ping;Zhang, Lingzi;Liu, Xinyong
通过铜催化的叠氮炔环加成（CuAAC）反应获得了含有3-羟基喹唑啉-2，4（1H，3 H）-二酮和1-羟基吡啶并[2，3-d]嘧啶-2（1H）-酮支架的小文库，并在MT-4细胞中评价了它们的抗HIV活性。在合成的化合物中，几种1-羟基吡啶并[2，3-d]嘧啶-2（1H）-酮衍生物显示出显著的抗HIV效力，EC 50值范围为0.92至26.85 μ M。其中活性最强的IIA-2对HIV 1型整合酶（IN）也表现出显著的选择性作用。据我们所知，这是第一个报告表明，1-羟基吡啶并[2，3-d]嘧啶-2（1H）-酮是选择性的HIV IN抑制剂。初步的构效关系（SAR）研究表明，二价金属离子螯合剂和取代基的性质和位置的核心是重要的抗病毒效力。分子模拟已被用于预测吡啶并[2，3-d]嘧啶-2（1H）-酮核心在HIV 1型IN中的结合位点，并为提高其抑制活性提出了建议。(C)2017爱思唯尔有限公司版权所有
A small library containing 3-hydroxyquinazoline-2,4(1H, 3H)-dione and 1-hydroxypyrido[2,3-d] pyrimidin- 2(1H)-one scaffolds was obtained via the copper(I)-catalyzed azidealkyne cycloaddition (CuAAC) reaction and evaluated for their anti-HIV activity in MT-4 cells. Among the synthesized compounds, several 1-hydroxypyrido[2,3-d] pyrimidin-2(1H)-one derivatives showed remarkable anti-HIV potency with EC50 values ranging from 0.92 to 26.85 mu M. The most active one, IIA-2, also showed remarkable and selective potency against HIV type 1 integrase (IN). To the best of our knowledge, this is the first report showing that 1-hydroxypyrido[2,3-d] pyrimidin-2(1H)-ones are selective HIV IN inhibitors. Preliminary structure-activity relationship (SAR) studies suggested that the divalent metal ion chelators and the nature and position of substituents around the core are important for antiviral potency. Molecular modeling has been used to predict the binding site of the pyrido[2,3-d] pyrimidin-2(1H)-one core in HIV type 1 IN and suggestions are made for improvement of its inhibitory activity. (C) 2017 Elsevier Ltd. All rights reserved.