Particulate matter with diameter ≤2.5 μm particles (PM2.5) can trigger pulmonary inflammation and lung injury. However, there is still no specific and effective treatment. Lansiumamide B (LB) is a natural cis-enamide compound isolated from wampee seeds, and has potential anti-inflammatory effect. Herein, two series of pyrazole enamide analogues were designed and synthesized based on the scaffold hopping strategy. The inhibition rates of inflammatory cytokines on compound 11a were superior to other compounds and exhibited good dose-dependent manner and safety. Mechanism studies shown that 11a activated the Keap1/Nrf2/HO-1 signaling pathway and promoted Nrf2 entering into nucleus. Further, 11a alleviated pulmonary inflammation, collagen formation and mucus secretion in PM2.5 induced lung injury mice. Besides, 11a administration inhibited M1 macrophage polarization and neutrophil infiltration. Overall, 11a is an effective anti-inflammatory agent which might be a potent candidate to treat lung injury.

中文翻译：

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新型吡唑烯酰胺类药物减轻肺损伤的合成、评价及机制研究


直径为 ≤2.5 μm 颗粒 （PM2.5） 的颗粒物会引发肺部炎症和肺损伤。然而，仍然没有特异性和有效的治疗方法。Lansiumamide B （LB） 是从 wampee 种子中分离的天然顺式烯酰胺化合物，具有潜在的抗炎作用。在此，基于支架跳跃策略设计合成了两个系列的吡唑烯酰胺类似物。炎性细胞因子对化合物 11a 的抑制率优于其他化合物，并表现出良好的剂量依赖性和安全性。机制研究表明，11a 激活 Keap1/Nrf2/HO-1 信号通路并促进 Nrf2 进入细胞核。此外，11a 减轻了 PM2.5 诱导的肺损伤小鼠的肺部炎症、胶原蛋白形成和粘液分泌。此外，11a 给药抑制 M1 巨噬细胞极化和中性粒细胞浸润。总体而言，11a 是一种有效的抗炎剂，可能是治疗肺损伤的有效候选药物。