Phthalide is a promising chemical scaffold and has been proved to show potent anti-inflammatory efficacy. In this study, three series, total of 31 novel phthalide derivatives were designed and synthesized, their anti-inflammatory activities were screened in vitro and in vivo. The anti-inflammatory activity of all the compounds were screened on LPS induced NO production to evaluating their inhibitory effects. Structure-activity relationship has been concluded, and finally 3-((4-((4-fluorobenzyl)oxy)phenyl)(hydroxy)methyl)-5,7-dimethoxyisobenzofuran-1 (3H)-one (compound 9o) was found to be the active one with low toxicity, which showed 95.23% inhibitory rate at 10 μM with IC₅₀ value of 0.76 μM against LPS-induced NO over expression. Preliminary mechanism studies indicated that compound 9o activated Nrf2/HO-1 signaling pathway via accumulation ROS and blocks the NF-κB/MAPK signaling pathway. The in vivo anti-inflammatory activity shown that compound 9o had obvious therapeutic effect against the adjuvant-induced rat arthritis model.

邻苯二甲酰胺是一种有前途的化学支架，并已被证明具有有效的抗炎功效。在这项研究中，设计并合成了三个系列的31种新型邻苯二甲酸酯衍生物，并在体内和体外筛选了它们的抗炎活性。筛选了所有化合物对LPS诱导的NO产生的抗炎活性，以评估其抑制作用。结构-活性关系已经结束，最后3 - （（4 - （（4-氟苄基）氧基）苯基）（羟基）甲基）-5,7-二dimethoxyisobenzofuran -1（3H） -酮（化合物90） ，发现成为一种低毒的活性化合物，在使用IC _{50的情况下}在10μM时显示出95.23％的抑制率LPS诱导的一氧化氮过表达值为0.76μM。初步的机理研究表明，化合物9o通过积累ROS激活了Nrf2 / HO-1信号通路，并阻断了NF-κB/ MAPK信号通路。体内抗炎活性表明，化合物9o对佐剂诱导的大鼠关节炎模型具有明显的治疗作用。