Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan 250012, China.
Centro de Biología Molecular "Severo Ochoa" (Consejo Superior de Investigaciones Científicas & Universidad Autónoma de Madrid), Madrid, Spain.
Bioorg Med Chem. 2019 Sep 1;27(17):3836-3845. doi: 10.1016/j.bmc.2019.07.011. Epub 2019 Jul 6.
A novel series of 3-hydroxyquinazoline-2,4(1H,3H)-diones derivatives has been designed and synthesized. Their biochemical characterization revealed that most of the compounds were effective inhibitors of HIV-1 RNase H activity at sub to low micromolar concentrations. Among them, II-4 was the most potent in enzymatic assays, showing an IC value of 0.41 ± 0.13 μM, almost five times lower than the IC obtained with β-thujaplicinol. In addition, II-4 was also effective in inhibiting HIV-1 IN strand transfer activity (IC = 0.85 ± 0.18 μM) but less potent than raltegravir (IC = 71 ± 14 nM). Despite its relatively low cytotoxicity, the efficiency of II-4 in cell culture was limited by its poor membrane permeability. Nevertheless, structure-activity relationships and molecular modeling studies confirmed the importance of tested 3-hydroxyquinazoline-2,4(1H,3H)-diones as useful leads for further optimization.
我们设计并合成了一系列新型 3-羟基喹唑啉-2,4(1H,3H)-二酮衍生物。它们的生化特性分析表明，大多数化合物在亚微摩尔浓度下就能有效抑制 HIV-1 RNase H 的活性。其中，化合物 II-4 的抑制效果最强，在酶促实验中的 IC 值为 0.41±0.13μM，几乎比 β-雪松醇的 IC 值低 5 倍。此外，化合物 II-4 还能有效抑制 HIV-1 IN 链转移活性（IC=0.85±0.18μM），但其抑制活性比雷特格韦（IC=71±14nM）弱。尽管 II-4 的细胞毒性相对较低，但由于其较差的膜透过性，其在细胞培养中的效率受到限制。然而，构效关系和分子建模研究证实了所测试的 3-羟基喹唑啉-2,4(1H,3H)-二酮作为进一步优化的有用先导化合物的重要性。
