Zhang Xiao-Fan, Luan Ming-Zhu, Yan Wei-Bin, Zhao Feng-Lan, Hou Yun, Hou Gui-Ge, Meng Qing-Guo
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, PR China.
School of Pharmacy, The Key Laboratory of Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine of China, Binzhou Medical University, Yantai, 264003, PR China.
Eur J Med Chem. 2022 May 5;235:114322. doi: 10.1016/j.ejmech.2022.114322. Epub 2022 Mar 26.
Neuroinflammation is an intricate process that is associated with both normal and pathological conditions. Microglia-mediated neuroinflammation is known to lead to various neurodegenerative and neurological disorders. A series of 3,4-dihydronaphthalen-1(2H)-one derivatives (1-15) and novel 5,6-dihydrobenzo[h]quinazolin-2-amine derivatives (16-30) were synthesized and characterized by various analytical methods, such as NMR and HRMS. All compounds were evaluated for toxicity, screened for their anti-neuroinflammatory properties, and investigated for the potential molecular mechanism of lipopolysaccharide (LPS) induction in BV2 microglia. Structure activity relationship analysis showed that compound 17 substituted by the 7-fluorine atom on the A-ring and the 3-methoxy on the D-ring had more potential anti-neuroinflammatory activity by inhibiting the secretion of cytokines TNF-α and IL-6. The results of western blotting assay showed that 17 significantly blocked the activation and phosphorylation of IκBα, significantly reduce the expression of NLRP3 inflammatory vesicle-associated proteins, and thus inhibit the activation of NF-κB pathway. Thus, compound 17 was demonstrated to be an excellent potential therapeutic agent for the treatment of neuroinflammation-related diseases.
神经炎症是一个复杂的过程，与正常和病理状况均相关。已知小胶质细胞介导的神经炎症会导致各种神经退行性疾病和神经疾病。合成了一系列3,4-二氢萘-1(2H)-酮衍生物（1-15）和新型5,6-二氢苯并[h]喹唑啉-2-胺衍生物（16-30），并通过多种分析方法（如核磁共振和高分辨质谱）进行了表征。对所有化合物进行了毒性评估，筛选了它们的抗神经炎症特性，并研究了脂多糖（LPS）诱导BV2小胶质细胞的潜在分子机制。构效关系分析表明，A环上被7-氟原子取代且D环上有3-甲氧基的化合物17通过抑制细胞因子TNF-α和IL-6的分泌具有更强的潜在抗神经炎症活性。蛋白质印迹分析结果表明，17显著阻断IκBα的激活和磷酸化，显著降低NLRP3炎性小体相关蛋白的表达，从而抑制NF-κB通路的激活。因此，化合物17被证明是治疗神经炎症相关疾病的一种极具潜力的治疗药物。
