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

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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 flip**. 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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Acknowledgements

This study was supported by Shaanxi University of Traditional Chinese Medicine Student Innovation and Entrepreneurship Training Program Project (No 202210716107). Shaanxi Province key research and development plan project (No. 2024SF-YBXM-487). Sci-Tech Innovation Talent System Construction Program of Shaanxi University of Chinese Medicine (No. 2023-CXTD-05). Shaanxi Special Support Plan Talent Project. Shaanxi Provincial Administration of Traditional Chinese Medicine “Double Chain Integration” Young and middle-aged Scientific Research and Innovation Team Project (2022-SLRH-YQ-008).

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Authors and Affiliations

  1. College of Pharmacy, Shaanxi University of Chinese Medicine, Shiji Ave., ** Liu, Yongheng Shi, ** Liu, Yongheng Shi & **nya Xu

  2. The Second Affiliated Hospital of Shaanxi University of Traditional Chinese Medicine, **anyang, PR China

    Peifeng Wei

  3. State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, East China University of Science and Technology, 130 Mei Long Road, Shanghai, 200237, PR China

    **lian Wei

  4. Institute of Translational Medicine, Shanghai University 99 Shangda Road, Shanghai, 200444, PR China

    Shipeng He

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  1. Yundong **e
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