{"title":"Mollugin Derivatives as Anti-Inflammatory Agents: Design, Synthesis, and NF-κB Inhibition","authors":"Yuan-Liang Gao, Ming-Yue Li, Da-Yuan Wang, Shi-Ang Jin, Xin-Yu Ma, Xue-Jun Jin, Hu-Ri Piao","doi":"10.1111/cbdd.70024","DOIUrl":null,"url":null,"abstract":"<div>\n \n <p>Nuclear factor κB (NF-κB) is a key inducible transcription factor that controls a large number of genes involved in inflammatory and immune processes. The entire inflammation-mediated process uses NF-κB as a hub, and inflammatory gene transcription and expression can be decreased by blocking the NF-κB signaling pathway, thereby reducing inflammatory damage. Therefore, the inhibition of this pathway is an important therapeutic target for the treatment of various types of inflammation. Here, we designed and synthesized 27 mollugin derivatives and evaluated the anti-inflammatory activity against NF-κB transcription. Most of the compounds exhibited potent anti-inflammatory activity, and compound <b>5k</b> was the most potent with 81.77% inhibition after intraperitoneal administration, which was significantly more potent than mollugin (49.72%), ibuprofen (47.51%), and mesalazine (47.24%). Investigation of the mechanism of action indicated that <b>5k</b> down-regulated NF-κB expression, possibly by suppressing LPS-induced expression of the p65 protein. ADMET prediction analysis indicated that compounds <b>5h</b> and <b>5k</b> showed good pharmacokinetic properties. The relationship between the structures of the synthesized compounds and the NF-κB inhibitory activity was rationalized using molecular docking simulation experiments. Overall, these results provide an initial basis for the development of <b>5h</b> and <b>5k</b> as potential anti-inflammatory agents.</p>\n </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 6","pages":""},"PeriodicalIF":3.2000,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Chemical Biology & Drug Design","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/cbdd.70024","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Nuclear factor κB (NF-κB) is a key inducible transcription factor that controls a large number of genes involved in inflammatory and immune processes. The entire inflammation-mediated process uses NF-κB as a hub, and inflammatory gene transcription and expression can be decreased by blocking the NF-κB signaling pathway, thereby reducing inflammatory damage. Therefore, the inhibition of this pathway is an important therapeutic target for the treatment of various types of inflammation. Here, we designed and synthesized 27 mollugin derivatives and evaluated the anti-inflammatory activity against NF-κB transcription. Most of the compounds exhibited potent anti-inflammatory activity, and compound 5k was the most potent with 81.77% inhibition after intraperitoneal administration, which was significantly more potent than mollugin (49.72%), ibuprofen (47.51%), and mesalazine (47.24%). Investigation of the mechanism of action indicated that 5k down-regulated NF-κB expression, possibly by suppressing LPS-induced expression of the p65 protein. ADMET prediction analysis indicated that compounds 5h and 5k showed good pharmacokinetic properties. The relationship between the structures of the synthesized compounds and the NF-κB inhibitory activity was rationalized using molecular docking simulation experiments. Overall, these results provide an initial basis for the development of 5h and 5k as potential anti-inflammatory agents.
期刊介绍:
Chemical Biology & Drug Design is a peer-reviewed scientific journal that is dedicated to the advancement of innovative science, technology and medicine with a focus on the multidisciplinary fields of chemical biology and drug design. It is the aim of Chemical Biology & Drug Design to capture significant research and drug discovery that highlights new concepts, insight and new findings within the scope of chemical biology and drug design.