Gao Ping, Zhang Lingzi, Sun Lin, Huang Tianguang, Tan Jing, Zhang Jian, Zhou Zhongxia, Zhao Tong, Menéndez-Arias Luis, Pannecouque Christophe, Clercq Erik De, Zhan Peng, Liu Xinyong
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012, Jinan, Shandong, PR China.
Centro de Biología Molecular "Severo Ochoa" (Consejo Superior de Investigaciones Científicas & Universidad Autónoma de Madrid), Madrid, Spain.
Bioorg Med Chem. 2017 Oct 15;25(20):5779-5789. doi: 10.1016/j.bmc.2017.09.006. Epub 2017 Sep 8.
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 EC values ranging from 0.92 to 26.85µM. 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.
通过铜（I）催化的叠氮化物-炔烃环加成（CuAAC）反应得到了一个包含3-羟基喹唑啉-2,4（1H，3H）-二酮和1-羟基吡啶并[2,3-d]嘧啶-2（1H）-酮支架的小型文库，并在MT-4细胞中评估了它们的抗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）-酮衍生物表现出显著的抗HIV效力，其EC值范围为0.92至26.85µM。活性最高的化合物IIA-2对1型HIV整合酶（IN）也表现出显著的选择性效力。据我们所知，这是首次报道1-羟基吡啶并[2,3-d]嘧啶-2（1H）-酮是选择性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以及核心周围取代基的性质和位置对抗病毒效力很重要。分子建模已用于预测吡啶并[2,3-d]嘧啶-2（1H）-酮核心在1型HIV IN中的结合位点，并对提高其抑制活性提出了建议。
