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

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

doi:10.1016/j.ejmech.2024.117068

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

Eur J Med Chem. 2024 Nov 15:282:117068. doi: 10.1016/j.ejmech.2024.117068. Online ahead of print.

Authors

Guoping Zhang¹, Mengjie Li², Yanghui Ou², Liya Ma¹, Jiayu Li², Kexin Sun¹, Tingting Xia³, Jingbo Wang³, Liyan Song⁴, Yang Liu⁵, Ran Lin⁶, Hongliang Yao⁷

Affiliations

¹ Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Shaanxi Key Laboratory for Animal Conservation, College of Life Science, Northwest University, Xi'an, Shaanxi, 710069, China; Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, Guangdong, 510260, China.
² Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, Guangdong, 510260, China.
³ Department of Biopharmaceutical Sciences, College of Bee Science and Biomedicine, Fujian Agriculture and Forestry University, Fuzhou, Fujian, 350002, China.
⁴ Key Laboratory of Biopesticide and Chemical Biology (Ministry of Education), College of Plant Protection, Fujian Agriculture and Forestry University, Fuzhou, Fujian, China.
⁵ Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Shaanxi Key Laboratory for Animal Conservation, College of Life Science, Northwest University, Xi'an, Shaanxi, 710069, China; Department of Entomology, University of Manitoba, Winnipeg, MB R3T 2N2, Canada. Electronic address: [email protected].
⁶ Department of Biopharmaceutical Sciences, College of Bee Science and Biomedicine, Fujian Agriculture and Forestry University, Fuzhou, Fujian, 350002, China. Electronic address: [email protected].
⁷ Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, Guangdong, 510260, China. Electronic address: [email protected].

PMID: 39561496
DOI: 10.1016/j.ejmech.2024.117068

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 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.

Keywords: Anti-Inflammation; Lung injury; Pyrazole enamides.