New Synthetic Quinolines as Cathepsin K Inhibitors

Cathepsin K is a papain-like cysteine protease and is responsible for collagen degradation in bone tissue and thus represents an important target for the development of new therapies for treating diseases such as osteoporosis. Quinolines are an important class of heterocyclic molecular leads with a great pharmacological potential and represent a relevant scaffold to explore the chemical space of cathepsin K (CatK) inhibitors. This study presents the synthesis of nine 2,4-diphenylquinolines, including five phthalonitrile quinolines dyads, and the evaluation of their CatK inhibitory activity. Among the evaluated compounds, 4b was the most potent inhibitor with an IC50 (half-maximal inhibitory concentration) value of 1.55 µM (against Z-Phe-Arg-MCA substrate) acting in an uncompetitive inhibition mode. Molecular docking studies provided important information on the interaction of the inhibitor with the enzyme showing that these quinoline derivatives can play an important role as CatK inhibitors.组织蛋白酶K（Cathepsin K，简称CatK）是一种木瓜蛋白酶样半胱氨酸蛋白酶，负责骨组织中的胶原蛋白降解，因此是开发骨质疏松症等疾病新型治疗手段的重要靶点。喹啉类化合物（Quinolines）是一类重要的杂环分子先导化合物，具备出色的药理潜力，是探索组织蛋白酶K（CatK）抑制剂化学空间的关键骨架母核。本研究完成了9种2,4-二苯基喹啉类化合物的合成，其中包含5种邻苯二甲腈喹啉二元体，并对其组织蛋白酶K抑制活性进行了评估。在所测试的化合物中，4b的抑制活性最强，针对Z-苯丙氨酸-精氨酸-甲基香豆素（Z-Phe-Arg-MCA）底物的半最大抑制浓度（half-maximal inhibitory concentration，IC50）为1.55 μM，且以非竞争性抑制模式发挥作用。分子对接研究为阐明抑制剂与酶的相互作用提供了重要信息，结果表明这类喹啉衍生物可作为组织蛋白酶K抑制剂发挥关键作用。