Design, synthesis, and anti-inflammatory activity of 2H-1,4-benzoxazin-3(4H)-one derivatives modified with 1,2,3-triazole in LPS-induced BV-2 cells
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. Screenin...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2024.1509520/full |
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| author | Xixi Hou Xixi Hou Longfei Mao Huibin Zhang Lan Wang Baoyu He Jingjing Guo Jianji Wang |
| author_facet | Xixi Hou Xixi Hou Longfei Mao Huibin Zhang Lan Wang Baoyu He Jingjing Guo Jianji Wang |
| author_sort | Xixi Hou |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-83a2609062a448dab8624789abb13c67 |
| institution | Kabale University |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj-art-83a2609062a448dab8624789abb13c672025-01-20T08:49:15ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-01-011510.3389/fphar.2024.15095201509520Design, synthesis, and anti-inflammatory activity of 2H-1,4-benzoxazin-3(4H)-one derivatives modified with 1,2,3-triazole in LPS-induced BV-2 cellsXixi Hou0Xixi Hou1Longfei Mao2Huibin Zhang3Lan Wang4Baoyu He5Jingjing Guo6Jianji Wang7Key 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, ChinaThe First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan, ChinaCollege of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, Henan, ChinaCollege of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, Henan, ChinaCollege of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, Henan, ChinaCentre for Artificial Intelligence Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macao, ChinaCentre for Artificial Intelligence Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macao, ChinaKey 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, ChinaGiven 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.https://www.frontiersin.org/articles/10.3389/fphar.2024.1509520/full1,2,3-triazoles2H-1,4-benzoxazin-3(4H)-onemicroglial cellsLPS-inducedantiinflammatory |
| spellingShingle | Xixi Hou Xixi Hou Longfei Mao Huibin Zhang Lan Wang Baoyu He Jingjing Guo Jianji Wang Design, synthesis, and anti-inflammatory activity of 2H-1,4-benzoxazin-3(4H)-one derivatives modified with 1,2,3-triazole in LPS-induced BV-2 cells Frontiers in Pharmacology 1,2,3-triazoles 2H-1,4-benzoxazin-3(4H)-one microglial cells LPS-induced antiinflammatory |
| title | Design, synthesis, and anti-inflammatory activity of 2H-1,4-benzoxazin-3(4H)-one derivatives modified with 1,2,3-triazole in LPS-induced BV-2 cells |
| title_full | Design, synthesis, and anti-inflammatory activity of 2H-1,4-benzoxazin-3(4H)-one derivatives modified with 1,2,3-triazole in LPS-induced BV-2 cells |
| title_fullStr | Design, synthesis, and anti-inflammatory activity of 2H-1,4-benzoxazin-3(4H)-one derivatives modified with 1,2,3-triazole in LPS-induced BV-2 cells |
| title_full_unstemmed | Design, synthesis, and anti-inflammatory activity of 2H-1,4-benzoxazin-3(4H)-one derivatives modified with 1,2,3-triazole in LPS-induced BV-2 cells |
| title_short | Design, synthesis, and anti-inflammatory activity of 2H-1,4-benzoxazin-3(4H)-one derivatives modified with 1,2,3-triazole in LPS-induced BV-2 cells |
| title_sort | design synthesis and anti inflammatory activity of 2h 1 4 benzoxazin 3 4h one derivatives modified with 1 2 3 triazole in lps induced bv 2 cells |
| topic | 1,2,3-triazoles 2H-1,4-benzoxazin-3(4H)-one microglial cells LPS-induced antiinflammatory |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2024.1509520/full |
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