Hou Xixi, Mao Longfei, Zhang Huibin, Wang Lan, He Baoyu, Guo Jingjing, Wang Jianji
Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan, China.
The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan, China.
Front Pharmacol. 2025 Jan 20;15:1509520. doi: 10.3389/fphar.2024.1509520. eCollection 2024.
Given the potent anti-inflammatory properties of the 1,2,3-triazole structure and the wide use of 2H-1,4-benzoxazin-3(4H)-one in developing treatments for neurodegenerative diseases, a series of 2H-1,4-benzoxazin-3(4H)-one derivatives were synthesized by introducing a 1,2,3-triazole moiety. Screening for anti-inflammatory activity in microglial cells revealed that compounds e2, e16, and e20 exhibited the most promising effects without significant cytotoxicity. These compounds effectively reduced LPS-induced NO production and significantly decreased the transcription levels of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α. Furthermore, they downregulated the transcription and protein levels of the inflammation-related enzymes iNOS and COX-2 in response to LPS stimulation. To further investigate the anti-inflammatory mechanisms of these derivatives in microglia, the intracellular ROS levels and the activation of the Nrf2-HO-1 signaling pathway were analyzed. The results indicated that the 2H-1,4-benzoxazin-3(4H)-one derivatives significantly activated the Nrf2-HO-1 pathway, reduced LPS-induced ROS production, and alleviated microglial inflammation. Molecular docking studies suggested that compounds e2, e16, and e20 could interact with Nrf2-related binding sites, preventing its degradation by Keap1. Additionally, acute toxicity tests in mice demonstrated that compound e16 exhibited favorable safety.
鉴于1,2,3-三唑结构具有强大的抗炎特性以及2H-1,4-苯并恶嗪-3(4H)-酮在神经退行性疾病治疗研发中的广泛应用，通过引入1,2,3-三唑部分合成了一系列2H-1,4-苯并恶嗪-3(4H)-酮衍生物。在小胶质细胞中进行的抗炎活性筛选显示，化合物e2、e16和e20表现出最有前景的效果且无明显细胞毒性。这些化合物有效降低了脂多糖诱导的一氧化氮生成，并显著降低了促炎细胞因子白细胞介素-1β、白细胞介素-6和肿瘤坏死因子-α的转录水平。此外，它们在脂多糖刺激下下调了炎症相关酶诱导型一氧化氮合酶和环氧化酶-2的转录和蛋白水平。为了进一步研究这些衍生物在小胶质细胞中的抗炎机制，分析了细胞内活性氧水平和Nrf2-HO-1信号通路的激活情况。结果表明，2H-1,4-苯并恶嗪-3(4H)-酮衍生物显著激活了Nrf2-HO-1通路，降低了脂多糖诱导的活性氧生成，并减轻了小胶质细胞炎症。分子对接研究表明，化合物e2、e16和e20可与Nrf2相关结合位点相互作用，防止其被Keap1降解。此外，小鼠急性毒性试验表明化合物e16具有良好的安全性。
