Discovery of 3, 6-disubstituted isobenzofuran-1(3H)-ones as novel inhibitors of monoamine oxidases

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 mu M and 0.32 mu M, 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.

Automated summary

Monoamine oxidases A and B (MAO-A and MAO-B) are important in biogenic amine metabolism, oxidative stress, and chronic inflammation. The study focused on designing and synthesizing novel compounds as inhibitors of MAO-A and MAO-B, and found that compounds with (R)-3-hydroxy pyrrolidine moiety showed preferable inhibition towards the MAO-B isoform. Among them, compound 6m with a 3',4'-difluorobenzyl ring on the 3-position showed the most potent MAO-B inhibitory activity. Compound 6m could be a new template structure for developing potent and selective MAO-B inhibitors.