Zhou Qian, Luo Wei-Hao, Zhang Bei, Xue Zhao-Hang, Huang Qing-Hua, Feng Ling-Ling, Wu Yinuo, Zhang Chen
Key Laboratory of Tropical Biological Resources of Ministry of Education and Hainan Engineering Research Center for Drug Screening and Evaluation, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, PR China.
School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan 528458, PR China.
Bioorg Chem. 2025 Jan;154:107979. doi: 10.1016/j.bioorg.2024.107979. Epub 2024 Nov 19.
Inflammatory bowel disease (IBD) is a chronic inflammatory disease that affects the entire gastrointestinal tract. The complex etiology of IBD made it difficult to cure. Phosphodiesterases (PDEs) have garnered significant attention due to their involvement in immune and inflammatory responses in IBD. Most recently, we have reported a novel PDE1 inhibitor 1 with quinolin-2(1H)-one scaffold, demonstrating anti-IBD effects. However, its short half-life (t) in the rat liver microsomes (RLMs) is relatively short. In this study, structural optimization of compound 1 was performed to improve metabolic stability. Combined with molecular docking and dynamics simulations, a series of quinolin-2(1H)-one derivatives were synthesized. Among them, compound 7a showed an excellent IC value of 11 nM, high selectivity to PDE1 compared to other PDEs, and good metabolic stability with RLM t of 67.3 min. The binding pattern between 7a and PDE1 revealed an additional hydrogen bond with Cys410, which could enhance the inhibitory activity. Furthermore, compound 7a demonstrated anti-inflammatory properties by reducing cytokine production and antioxidant activity in LPS-induced Raw264.7 cells, which contributed to its effectiveness against IBD. We believe that compound 7a could serve as an ideal tool for further pharmacological research on IBD.
炎症性肠病（IBD）是一种影响整个胃肠道的慢性炎症性疾病。IBD复杂的病因使其难以治愈。磷酸二酯酶（PDEs）因其参与IBD的免疫和炎症反应而备受关注。最近，我们报道了一种具有喹啉-2(1H)-酮骨架的新型PDE1抑制剂1，其具有抗IBD作用。然而，它在大鼠肝微粒体（RLMs）中的半衰期（t）相对较短。在本研究中，对化合物1进行了结构优化以提高代谢稳定性。结合分子对接和动力学模拟，合成了一系列喹啉-2(1H)-酮衍生物。其中，化合物7a显示出优异的IC值，为11 nM，与其他PDEs相比对PDE1具有高选择性，并且在RLMs中的代谢稳定性良好，t为67.3分钟。7a与PDE1之间的结合模式显示与Cys410形成了一个额外的氢键，这可以增强抑制活性。此外，化合物7a通过减少LPS诱导的Raw264.7细胞中的细胞因子产生和抗氧化活性而表现出抗炎特性，这有助于其对IBD的有效性。我们认为化合物7a可作为进一步开展IBD药理学研究的理想工具。
