Synthesis and biological evaluation of lappaconitine analogues as potential anti-neuroinflammatory agents by side chain modification and scaffold hopping strategy

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry Pub Date : 2024-11-20 DOI:10.1016/j.bmc.2024.118012

Feng Xing , Hong-Yi Su , He-Yang Zhong , Yu-Zhu Li , Yin-Yong Zhang , Lin Chen , Xian-Li Zhou

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Abstract

Neuroinflammation mediated by microglia is widely recognized as a key pathophysiological mechanism in neurodegenerative diseases. Lappaconitine (LA) is a natural C₁₈-diterpenoid alkaloid isolated from Aconitum sinomontanum Nakai, and previous study showed that LA and its derivatives inhibited lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 cells. However, the anti-neuroinflammatory effects of LA and its derivatives on microglia are still not clear. Here, LA analogues were designed and synthesized, and the anti-neuroinflammatory activity of the synthesized compounds was screened using LPS-induced overexpression of NO in BV-2 microglia. The screening results showed that compound 10 displayed the highest ability to inhibit NO production (IC₅₀ = 9.98 ± 1.6 µM). Mechanistic investigations revealed that compound 10 attenuated LPS-activated neuroinflammation through suppression of TLR4/MyD88/NF-κB pathway in BV-2 microglia. Acute toxicity assays showed that compound 10 (LD₅₀ = 508.1 mg/kg) was safer relative to LA (LD₅₀ = 30.6 mg/kg). Collectively, our findings show that compound 10 could have potential as anti-neuroinflammatory agents.

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通过侧链修饰和支架跳跃策略合成拉帕康尼汀类似物并对其进行生物学评估，使其成为潜在的抗神经炎药物

由小胶质细胞介导的神经炎症被广泛认为是神经退行性疾病的一个关键病理生理机制。先前的研究表明，LA 及其衍生物可抑制脂多糖（LPS）诱导的 RAW264.7 细胞一氧化氮（NO）的产生。然而，LA 及其衍生物对小胶质细胞的抗神经炎作用仍不明确。本文设计并合成了 LA 类似物，并利用 LPS 诱导的 BV-2 小胶质细胞一氧化氮过表达筛选了合成化合物的抗神经炎活性。筛选结果表明，化合物 10 抑制 NO 生成的能力最强（IC50 = 9.98 ± 1.6 µM）。机理研究发现，化合物 10 通过抑制 BV-2 小胶质细胞中的 TLR4/MyD88/NF-κB 通路，减轻了 LPS 激活的神经炎症。急性毒性实验表明，化合物 10（LD50 = 508.1 mg/kg）比 LA（LD50 = 30.6 mg/kg）更安全。总之，我们的研究结果表明，化合物 10 具有作为抗神经炎药物的潜力。

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来源期刊

Bioorganic & Medicinal Chemistry 医学-生化与分子生物学

CiteScore

6.80

自引率

2.90%

发文量

413

审稿时长

17 days

期刊介绍： Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides. The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.