Structural simplification and ester bond flipping lead to bis-benzodioxole derivatives as potential hypolipidemic and hepatoprotective agent

IF 2.6 4区医学 Q3 CHEMISTRY, MEDICINAL

Medicinal Chemistry Research Pub Date : 2024-05-22 DOI:10.1007/s00044-024-03216-0

Yundong Xie, Siyao Wang, Mengfei Sun, Yan Pang, Jiping Liu, Yongheng Shi, Xinya Xu, Peifeng Wei, Jinlian Wei, Shipeng He

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Abstract

A series of bis-benzodioxole derivatives was designed, synthesized, and evaluated. These target compounds were designed through structure simplification and ester bond flipping. The lipid-lowering activity of these target compounds was preliminarily evaluated in a hyperlipidemic mouse model induced by Triton WR 1339. The results showed that piperonylic acid -6-(3,4-methylenedioxyphenoxy) hexyl ester (T5) possesses notable lipid-lowering properties, reducing triglyceride (TG) and total cholesterol (TC) levels. The dose-dependent study revealed that compound T5 decreased TG and TC more strongly with the increase of dose. It was observed that T5 had considerable effects on decreasing TG, TC and low density lipoprotein cholesterol (LDL-C) levels in hyperlipidemic mice induced by high fat diet (HFD). Meanwhile, T5 was found to have hepatoprotective activity, with the liver aspartate transaminase (AST) and alanine aminotransferase (ALT) significantly decreasing and histopathological observation showing that it inhibited lipids accumulation in the liver and alleviated liver injury. T5 has been shown to stimulate peroxisome proliferator-activated receptor-α (PPAR-α) and suppress hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase in the liver in connection to lipid metabolism. The molecular docking study also revealed that T5 has a high affinity for the active sites of PPAR-α and HMG-CoA reductase. Furthermore, other beneficial activities, including antioxidation and anti-inflammation, were also noted. It is possible that further exploration may result in compound T5 becoming a promising candidate for lipid-lowering therapy.

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通过结构简化和酯键翻转，双苯并二恶茂衍生物成为潜在的降脂药和保肝药

我们设计、合成并评估了一系列双苯并二恶茂衍生物。这些目标化合物是通过结构简化和酯键翻转设计出来的。在 Triton WR 1339 诱导的高脂血症小鼠模型中，对这些目标化合物的降脂活性进行了初步评估。结果表明，胡椒酸-6-（3,4-亚甲二氧基苯氧基）己酯（T5）具有显著的降脂特性，可降低甘油三酯（TG）和总胆固醇（TC）水平。剂量依赖性研究表明，随着剂量的增加，化合物 T5 对甘油三酯和总胆固醇的降低作用更强。研究发现，T5 对降低高脂饮食（HFD）诱导的高脂血症小鼠的甘油三酯（TG）、总胆固醇（TC）和低密度脂蛋白胆固醇（LDL-C）水平有显著效果。同时，研究还发现 T5 具有保肝活性，肝脏天冬氨酸转氨酶（AST）和丙氨酸氨基转移酶（ALT）明显下降，组织病理学观察表明，T5 可抑制肝脏中的脂质积累，减轻肝损伤。研究表明，T5 能刺激肝脏中与脂质代谢有关的过氧化物酶体增殖激活受体-α（PPAR-α）和抑制肝脏中的羟甲基戊二酰辅酶 A（HMG-CoA）还原酶。分子对接研究还发现，T5 与 PPAR-α 和 HMG-CoA 还原酶的活性位点具有很高的亲和力。此外，还发现了其他有益的活性，包括抗氧化和抗炎。通过进一步研究，化合物 T5 有可能成为降脂疗法的理想候选药物。

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来源期刊

Medicinal Chemistry Research 医学-医药化学

CiteScore

4.70

自引率

3.80%

发文量

162

审稿时长

5.0 months

期刊介绍： Medicinal Chemistry Research (MCRE) publishes papers on a wide range of topics, favoring research with significant, new, and up-to-date information. Although the journal has a demanding peer review process, MCRE still boasts rapid publication, due in part, to the length of the submissions. The journal publishes significant research on various topics, many of which emphasize the structure-activity relationships of molecular biology.