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

A series of dietary flavonoid acacetin 7--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 , , , and were the most potent with a Ki of 37 to 68 nM against MAO-B. Compounds - displayed more than a thousand-fold selectivity index towards MAO-B compared with MAO-A. Moreover, compounds and 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.