Design, synthesis, and investigation of lipid-lowering and hepatoprotective effects of clofibrate-vanillin derivative based on structural optimization

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-06-14 DOI:10.1016/j.bmcl.2025.130309

Yumiao Song , Xinyi Shi , Xinyu Zhang , Ling Ding , Huizi Shangguan , Xin Wang , Jiping Liu , Yongheng Shi , Xinya Xu , Yundong Xie

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Abstract

The study aimed to optimize the structure of clofibrate to create a lipid-lowering medication with reduced liver damage properties. A new compound, clofibrate-vanillin (CF-Vanillin), was synthesized and tested in hyperlipidemic mice. The results showed that CF-Vanillin significantly reduce triglycerides (TG) and total cholesterol (TC), which was stronger than that of CF. The molecular docking results suggested that CF-Vanillin exhibits a favorable affinity towards PPAR-α. The results of the liver damage evaluation showed that CF-Vanillin significantly reduced liver damage compared to CF. The liver weight and liver coefficient of the CF-Vanillin group mice were significantly reduced (P < 0.01). The levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were significantly reduced (P < 0.05). Pathological analysis of liver tissue revealed a notable decrease in nuclear deformation, dissolution, inflammatory cell infiltration, and necrosis among mice treated with CF-Vanillin. Investigation into the liver damage reduction mechanism revealed a significant upregulation of Nrf2 and HO-1 expression (P < 0.01) in the liver tissue of CF-Vanillin group mice. Furthermore, CF-Vanillin exhibited notable antioxidant and anti-inflammatory properties. The results imply that CF-Vanillin shows improved lipid-lowering effects and decreased liver damage possibly due to its antioxidant and anti-inflammatory actions by activating the Nrf2/HO-1 signaling pathway.

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基于结构优化的氯贝特-香兰素衍生物降脂保肝作用的设计、合成与研究

该研究旨在优化氯贝特的结构，以创造一种降低肝损伤特性的降脂药物。合成了一种新的化合物氯贝特-香兰素（CF-Vanillin），并在高脂血症小鼠中进行了实验。结果表明，CF-香兰素对甘油三酯（TG）和总胆固醇（TC）的降低作用强于CF。分子对接结果表明，CF-香兰素对PPAR-α具有良好的亲和力。肝损伤评价结果显示，与CF相比，CF-香兰素显著减轻了肝损伤，CF-香兰素组小鼠肝脏重量和肝脏系数显著降低(P <；0.01)。谷草转氨酶（AST）和丙氨酸转氨酶（ALT）水平显著降低(P <；0.05)。肝组织病理分析显示，肝组织核变形、溶解、炎症细胞浸润和坏死明显减少。对肝损伤减轻机制的研究发现，Nrf2和HO-1的表达显著上调(P <；0.01)。此外，cf -香兰素具有显著的抗氧化和抗炎作用。结果表明，cf -香兰素可能通过激活Nrf2/HO-1信号通路，具有抗氧化和抗炎作用，具有改善降脂和减轻肝损伤的作用。

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.