Optimization of clofibrate with natural product sesamol for reducing liver injury induced by acetaminophen

AbstractAcetaminophen (APAP), which is widely used for the treatment of analgesic-antipyretic as the first-line drug, can cause extensive hepatic injury and even acute hepatic failure. Oxidative stress and inflammation have been considered as the main mechanism of hepatotoxicity. However, the only antidote available for clinical application is N-acetylcysteine at present, but it has side effects and may have no effect after a high dose. Although other reported compounds have detoxification effects, which suffer from problems caused by the relatively high dose, unclear mechanisms, or being evaluation. In order to obtain a better antidote, we used natural product sesamol as the dominant fragment to redevelop clofibrate, an old lipid-lowering drug, and obtained the target compound clofibrate-sesamol (CF-S) by molecular hybridization strategy. Biological studies showed that CF-S can not only significantly improve liver function indexes, but also obviously reduce liver tissue damage. Relevant mechanisms showed that CF-S could significantly increase the expression of Nrf2 in liver tissue, and significantly reduce the phosphorylation of NF- κB p65. CF-S may reduce the hepatotoxicity induced by APAP through the Nrf2/NF-κB signaling pathway.Graphical abstract

Source: Medicinal Chemistry Research - January 1, 2023 Category: Chemistry Source Type: research