Design, synthesis and biological evaluation of Alisol B derivatives for potential treatment of non-alcoholic steatohepatitis

Non-alcoholic fatty liver disease (NAFLD), also known as metabolic dysfunction- associated with fatty liver disease (MAFLD), is one of the most prevalent chronic liver diseases globally. NAFLD is characterized by the accumulation of liver fat unrelated to excessive alcohol consumption. Non-alcoholic steatohepatitis (NASH) is the disease progression of NAFLD and could develop into cirrhosis and hepatocellular carcinoma. In previous studies, the preclinical efficacy of alisol B and alisol B 23-acetate against NASH and metabolic syndrome was identified. However, there is a paucity of literature pertaining to the specialized structural optimization of alisol B for the treatment of NASH. In this study, a series of alisol B derivatives (1–21) were designed, synthesized and evaluated in order to improve the activity of alisol B and to obtain candidate compounds for treating NASH. The effects of the synthesized compounds on de novo lipogenesis and α-SMA gene expression were tested to explore the preliminary structure–activity relationship (SAR). Compounds 14 and 21 were selected for further in vivo investigation. The high-fat diet plus carbon tetrachloride (HFD + CCl₄)-induced NASH mice model was employed for biological evaluation in vivo. Compounds 14 and 21 effectively improved hepatic steatosis, ballooning, inflammatory infiltration, and hepatic fibrosis in the livers of HFD + CCl₄ mice. Thus, 14 and 21 are promising lead compounds for the treatment of NASH.