Synthesis and Biological Evaluation of 2-Phenoxyacetamide Analogues, a Novel Class of Potent and Selective Monoamine Oxidase Inhibitors

Monoamine oxidases (EC 1.4.3.4; MAOs), a family of FAD-containing enzymes, is an important target for antidepressant drugs. In this paper, a series of 2-phenoxyacetamide analogues were synthesized, and their inhibitory potency towards monoamine oxidases A (MAO-A) and B (MAO-B) were evaluated using enzyme and cancer cell lysate. 2-(4-Methoxyphenoxy)acetamide (compound 12) (SI = 245) and (2-(4-((prop-2-ynylimino)methyl)phenoxy)acetamide (compound 21) (IC(50MAO-A) = 0.018 μM, IC(50MAO-B) = 0.07 μM) were successfully identified as the most specific MAO-A inhibitor, and the most potent MAO-A/-B inhibitor, respectively. The inhibitory activities of these two compounds in living cells were also further evaluated utilizing HepG2 and SHSY-5Y cell lysates.