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Previously synthesized novel chalcone oxime ethers (COEs) were evaluated for inhibitory activities against monoamine oxidases (MAOs) and acetylcholinesterase (AChE). Twenty-two of the 24 COEs synthesized, except <b>COE-17</b> and <b>COE-24</b>, had potent and/or significant selective inhibitory effects on MAO-B. <b>COE-6</b> potently inhibited MAO-B with an IC₅₀ value of 0.018 µM, which was 105, 2.3, and 1.1 times more potent than clorgyline, lazabemide, and pargyline (reference drugs), respectively. <b>COE-7</b>, and <b>COE-22</b> were also active against MAO-B, both had an IC₅₀ value of 0.028 µM, which was 67 and 1.5 times lower than those of clorgyline and lazabemide, respectively. Most of the COEs exhibited weak inhibitory effects on MAO-A and AChE. <b>COE-13</b> most potently inhibited MAO-A (IC₅₀ = 0.88 µM) and also significantly inhibited MAO-B (IC₅₀ = 0.13 µM), and it could be considered as a potential nonselective MAO inhibitor. <b>COE-19</b> and <b>COE-22</b> inhibited AChE with IC₅₀ values of 5.35 and 4.39 µM, respectively. The selectivity index (SI) of <b>COE-22</b> for MAO-B was higher than that of <b>COE-6</b> (SI = 778.6 vs. 222.2), but the IC₅₀ value (0.028 µM) was slightly lower than that of <b>COE-6</b> (0.018 µM). In reversibility experiments, inhibitions of MAO-B by <b>COE-6</b> and <b>COE-22</b> were recovered to the levels of reference reversible inhibitors and both competitively inhibited MAO-B, with K_i values of 0.0075 and 0.010 µM, respectively. Our results show that <b>COE-6</b> and <b>COE-22</b> are potent, selective MAO-B inhibitors, and <b>COE-22</b> is a candidate of dual-targeting molecule for MAO-B and AChE.