Department of Organic Chemistry, Faculty of Chemistry, Voronezh State University, 1 Universitetskaya sq., 394018 Voronezh, Russia.
Research Computing Center, Lomonosov Moscow State University, 119992 Moscow, Russia.
Molecules. 2020 Apr 19;25(8):1889. doi: 10.3390/molecules25081889.
Coagulation factor Xa and factor XIa are proven to be convenient and crucial protein targets for treatment for thrombotic disorders and thereby their inhibitors can serve as effective anticoagulant drugs. In the present work, we focused on the structure-activity relationships of derivatives of pyrrolo[3,2,1-]quinolin-2(1)-one and an evaluation of their activity against factor Xa and factor XIa. For this, docking-guided synthesis of nine compounds based on pyrrolo[3,2,1-]quinolin-2(1)-one was carried out. For the synthesis of new hybrid hydropyrrolo[3,2,1-]quinolin-2(1)-one derivatives, we used convenient structural modification of both the tetrahydro- and dihydroquinoline moiety by varying the substituents at the C positions. In vitro testing revealed that four derivatives were able to inhibit both coagulation factors and three compounds were selective factor XIa inhibitors. An IC value of 3.68 μM for was found for the best factor Xa inhibitor and 2 μM for the best factor XIa inhibitor.
凝血因子 Xa 和因子 XIa 已被证明是治疗血栓性疾病的方便且重要的蛋白质靶标，因此它们的抑制剂可以作为有效的抗凝药物。在本工作中，我们专注于吡咯并[3,2,1-]喹啉-2(1)-酮衍生物的构效关系及其对因子 Xa 和因子 XIa 的活性评估。为此，我们基于吡咯并[3,2,1-]喹啉-2(1)-酮进行了九种化合物的基于对接指导的合成。为了合成新型杂合氢吡咯并[3,2,1-]喹啉-2(1)-酮衍生物，我们通过改变 C 位置的取代基方便地对四氢和二氢喹啉部分进行了结构修饰。体外测试表明，有四种衍生物能够抑制两种凝血因子，有三种化合物是因子 XIa 的选择性抑制剂。最佳因子 Xa 抑制剂的 IC 值为 3.68 μM，最佳因子 XIa 抑制剂的 IC 值为 2 μM。
