Computationally Assisted Lead Optimization of Novel Potent and Selective MAO-B Inhibitors

A series of dietary flavonoid acacetin 7-O-methyl ether derivatives were computationally designed aiming to improve the selectivity and potency profiles against monoamine oxidase (MAO) B. The designed compounds were evaluated for their potential to inhibit human MAO-A and -B. Compounds 1c, 2c, 3c, and 4c were the most potent with a Ki of 37 to 68 nM against MAO-B. Compounds 1c-4c displayed more than a thousand-fold selectivity index towards MAO-B compared with MAO-A. Moreover, compounds 1c and 2c showed reversible inhibition of MAO-B. These results provide a basis for further studies on the potential application of these modified flavonoids for the treatment of Parkinson's Disease and other neurological disorders.

Automated summary

A series of dietary flavonoid acacetin 7-O-methyl ether derivatives were computationally designed to improve selectivity and potency against monoamine oxidase (MAO) B. Compounds 1c, 2c, 3c, and 4c showed potent inhibition against MAO-B with over a thousand-fold selectivity compared to MAO-A. Compounds 1c and 2c also displayed reversible inhibition of MAO-B, suggesting potential therapeutic applications for Parkinson's Disease and other neurological disorders.