Morpholine-based chalcones as dual-acting monoamine oxidase-B and acetylcholinesterase inhibitors: synthesis and biochemical investigations

Abstract

Nine compounds (<b>MO1-MO9</b>) containing the morpholine moiety were assessed for their inhibitory activities against monoamine oxidases (MAOs) and acetylcholinesterase (AChE). Most of the compounds potently inhibited MAO-B; <b>MO1</b> most potently inhibited with an IC₅₀ value of 0.030 µM, followed by <b>MO7</b> (0.25 µM). <b>MO5</b> most potently inhibited AChE (IC₅₀ = 6.1 µM), followed by <b>MO9</b> (IC₅₀ = 12.01 µM) and <b>MO7</b> most potently inhibited MAO-A (IC₅₀ = 7.1 µM). <b>MO1</b> was a reversible mixed-type inhibitor of MAO-B (<i>K_i</i> = 0.018 µM); <b>MO5</b> reversibly competitively inhibited AChE (<i>K_i</i> = 2.52 µM); and <b>MO9</b> reversibly noncompetitively inhibited AChE (<i>K_i</i> = 7.04 µM). <b>MO1</b>, <b>MO5</b> and <b>MO9</b> crossed the blood-brain barrier, and were non-toxic to normal VERO cells. These results show that <b>MO1</b> is a selective inhibitor of MAO-B and that <b>MO5</b> is a dual-acting inhibitor of AChE and MAO-B, and that both should be considered candidates for the treatment of Alzheimer's disease.