Monoamine oxidases A and B (MAO-A and MAO-B) play important roles in biogenic amine metabolism, oxidative stress, and chronic inflammation. Particularly, MAO-B selective inhibitors are promising therapeutic choices for the treatment of neurodegenerative diseases, such as Pakinson’s disease and Alzheimer’s disease. Herein, novel 3,6-disubstituted isobenzofuran-1(3H)-ones were designed, synthesized and evaluated in vitro as inhibitors of monoamine oxidases A and B. Structure-activity relationships were investigated, and all of the compounds with (R)-3-hydroxy pyrrolidine moiety on the 6-position displayed preferable inhibition toward the MAO-B isoform. Among them, compounds 6c with a 4′-fluorobenzyl ring and 6m bearing a 3′,4′-difluorobenzyl ring on the 3-position were the most potent MAO-B inhibitors with IC₅₀ values of 0.35 μM and 0.32 μM, respectively. The binding mode of compound 6m in MAO-B was predicted by CDOCKER program, revealing that (R)-3-hydroxypyrrolidine moiety is a critical structural feature for this series of MAO-B inhibitors. Compound 6m could serve as a new template structure for developing potent and selective MAO-B inhibitors.

单胺氧化酶 A 和 B（MAO-A 和 MAO-B）在生物胺代谢、氧化应激和慢性炎症中起重要作用。特别是，MAO-B 选择性抑制剂是治疗神经退行性疾病，如帕金森病和阿尔茨海默病的有希望的治疗选择。在此，设计、合成了新型 3,6-二取代异苯并呋喃-1(3 H )-ones 作为单胺氧化酶 A 和 B 的抑制剂，并在体外对其进行了评估。研究了结构-活性关系，所有具有 ( R )的化合物6 位上的-3-羟基吡咯烷部分对 MAO-B 异构体表现出较好的抑制作用。其中，化合物6c具有 4'-氟苄基环和6m在 3 位带有 3',4'-二氟苄基环是最有效的 MAO-B 抑制剂，IC ₅₀值分别为 0.35 μM 和 0.32 μM。通过CDOCKER程序预测了化合物6m在MAO-B中的结合模式，揭示了( R )-3-羟基吡咯烷部分是该系列MAO-B抑制剂的关键结构特征。化合物6m可作为开发有效和选择性 MAO-B 抑制剂的新模板结构。