Novel 1,8-naphthyridine-2-carboxamide derivatives with various substituents (HSR2101-HSR2113) were synthesized and evaluated for their effects on the production of pro-inflammatory mediators and cell migration in lipopolysaccharide (LPS)-treated BV2 microglial cells. Among the tested compounds, HSR2104 exhibited the most potent inhibitory effects on the LPS-stimulated production of inflammatory mediators, including nitric oxide (NO), tumor necrosis factor-α, and interleukin-6. Therefore, this compound was chosen for further investigation. We found that HSR2104 attenuated levels of inducible NO synthase and cyclooxygenase 2 in LPS-treated BV2 cells. In addition, it markedly suppressed LPS-induced cell migration as well as the generation of intracellular reactive oxygen species (ROS). Moreover, HSR2104 abated the LPS-triggered nuclear translocation of nuclear factor-κB (NF-κB) through inhibition of inhibitor kappa Bα phosphorylation. Furthermore, it reduced the expressions of Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) in LPS-treated BV2 cells. Similar results were observed with TAK242, a specific inhibitor of TLR4, suggesting that TLR4 is an upstream regulator of NF-κB signaling in BV2 cells. Collectively, our findings demonstrate that HSR2104 exhibits anti-inflammatory and anti-migratory activities in LPS-treated BV2 cells via the suppression of ROS and TLR4/MyD88/NF-κB signaling pathway. Based on our observations, HSR2104 may have a beneficial impact on inflammatory responses and microglial cell migration involved in the pathogenesis of various neurodegenerative disorders.

中文翻译：

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新型的1,8-萘啶-2-羧酰胺衍生物通过抑制ROS的产生和TLR4 / Myd88 /NF-κB信号通路抑制LPS处理的BV2细胞的炎症反应和细胞迁移。

合成了具有各种取代基的新型1,8-萘啶-2-羧酰胺衍生物（HSR2101-HSR2113），并评估了它们对促炎性介质产生和脂多糖（LPS）处理的BV2小胶质细胞中细胞迁移的影响。在测试的化合物中，HSR2104对LPS刺激的炎症介质（包括一氧化氮（NO），肿瘤坏死因子-α和白介素6）的产生具有最强的抑制作用。因此，选择该化合物用于进一步研究。我们发现，HSR2104降低了LPS处理的BV2细胞中诱导型NO合酶和环氧合酶2的水平。此外，它显着抑制LPS诱导的细胞迁移以及细胞内活性氧（ROS）的产生。而且，HSR2104通过抑制抑制剂KappaBα磷酸化，减轻了LPS触发的核因子-κB（NF-κB）的核易位。此外，它降低了LPS处理的BV2细胞中Toll样受体4（TLR4）和髓样分化因子88（MyD88）的表达。用TAK242（一种TLR4的特异性抑制剂）观察到了相似的结果，这表明TLR4是BV2细胞中NF-κB信号传导的上游调节剂。总体而言，我们的发现表明HSR2104通过抑制ROS和TLR4 / MyD88 /NF-κB信号通路在LPS处理的BV2细胞中表现出抗炎和抗迁移活性。根据我们的观察，HSR2104可能对各种神经退行性疾病的发病机制中涉及的炎症反应和小胶质细胞迁移产生有益影响。