Synthesis, evaluation and mechanism study of novel pyrazole enamides to alleviate lung injury

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2024-11-15 DOI:10.1016/j.ejmech.2024.117068

Guoping Zhang, Mengjie Li, Yanghui Ou, Liya Ma, Jiayu Li, Kexin Sun, Tingting Xia, Jingbo Wang, Liyan Song, Yang Liu, Ran Lin, Hongliang Yao

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引用次数: 0

Abstract

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 promoted sputum 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.

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缓解肺损伤的新型吡唑酰胺的合成、评估和机理研究

直径≤ 2.5 μm 的颗粒物（PM2.5）可引发肺部炎症和肺损伤。然而，目前仍没有特异性的有效治疗方法。兰硫酰胺 B（LB）是从芒皮种子中分离出来的一种天然顺烯酰胺化合物，具有潜在的抗炎作用。本文基于支架跳转策略设计并合成了两个系列的吡唑烯酰胺类似物。化合物 11a 对炎症细胞因子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。机理研究表明，11a 激活了 Keap1/Nrf2/HO-1 信号通路，并促进 Nrf2 进入细胞核。此外，11a 还能缓解 PM2.5 诱导的肺损伤小鼠的肺部炎症、胶原形成并促进痰液分泌。此外，11a 还能抑制 M1 巨噬细胞极化和中性粒细胞浸润。总之，11a 是一种有效的抗炎药物，可能是治疗肺损伤的有效候选药物。

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.