Discovery of 3-Hydroxy-3-phenacyloxindole Analogues of Isatin as Potential Monoamine Oxidase Inhibitors.

A series of 3-hydroxy-3-phenacyloxindole analogues of isatin were designed, synthesized, and evaluated in vitro for their inhibitory activity toward monoamine oxidase (MAO) A and B. Most of the synthesized compounds proved to be potent and selective inhibitors of MAO-A rather than MAO-B. 1-Benzyl-3-hydroxy-3-(4'-hydroxyphenacyl)oxindole (compound 18) showed the highest MAO-A inhibitory activity (IC50 : 0.009 ± 0.001 μM, Ki : 3.69 ± 0.003 nM) and good selectivity (selectivity index: 60.44). Kinetic studies revealed that compounds 18 and 16 (1-benzyl-3-hydroxy-3-(4'-bromophenacyl)oxindole) exhibit competitive inhibition against MAO-A and MAO-B, respectively. Structure-activity relationship studies suggested that the 3-hydroxy group is an essential feature for these analogues to exhibit potent MAO-A inhibitory activity. Computational studies revealed the possible molecular interactions between the inhibitors and MAO isozymes. The computational data obtained are congruent with experimental results. Further studies on the lead inhibitors, including co-crystallization of inhibitor-MAO complexes and in vivo evaluations, are essential for their development as potential therapeutic agents for the treatment of MAO-associated neurological disorders.