Phthalides and Norphthalides From the Ethyl Acetate Extracts of Ligusticum chuanxiong and Their Inhibitory Effects on Xanthine Oxidase In Vitro

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Four unreported compounds (1-4) and five known compounds (5-9) were isolated from ethyl acetate extracts of Ligusticum chuanxiong by a silica gel column chromatography, Sephadex LH-20 column chromatography, and semi-preparative HPLC. The planar structures of compounds 1-4 were confirmed by analyzing their HR-ESIMS, IR, and NMR spectra. Compounds 1 and 2 feature a norphthalide mono-ring skeleton derived from phthalide by the loss of one carbon atom. In addition, the absolute configurations of compounds 1-4 were elucidated by comparing their experimental and calculated electronic circular dichroism (ECD) spectra. The results of xanthine oxidase (XO) inhibitory activities in vitro revealed seven compounds (1-4, 6-8) exhibited notable inhibitory activities on XO, which was validated by the molecular docking results. In particular, compounds 4 and 7 possessed excellent activities. Further structure-activity relationship indicated that the hydroxyl, carbonyl, and C3═C8 double bond of phthalides have an important influence on XO inhibitory activities. This study is the first report of norphthalides and phthalides from ethyl acetate extracts of Ligusticum chuanxiong demonstrating XO inhibitory activities and their structure-activity relationship, thereby providing important insights for the discovery of novel and safe therapeutic agents for gout and hyperuricemia from natural products.