| Summary: | Monoamine oxidase-B (MAO-B), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) have been considered target enzymes of depression and neurodegenerative diseases, including Alzheimer’s disease (AD). In this study, seventeen <i>N</i>-methyl-piperazine chalcones were synthesized, and their inhibitory activities were evaluated against the target enzymes. Compound <b>2k</b> (3-trifluoromethyl-4-fluorinated derivative) showed the highest selective inhibition against MAO-B with an IC<sub>50</sub> of 0.71 μM and selectivity index (SI) of 56.34, followed by <b>2n</b> (2-fluoro-5-bromophenyl derivative) (IC<sub>50</sub> = 1.11 μM, SI = 16.04). Compounds <b>2k</b> and <b>2n</b> were reversible competitive MAO-B inhibitors with K<sub>i</sub> values of 0.21 and 0.28 μM, respectively. Moreover, <b>2k</b> and <b>2n</b> effectively inhibited AChE with IC<sub>50</sub> of 8.10 and 4.32 μM, which underscored their multi-target inhibitory modes. Interestingly, compound <b>2o</b> elicited remarkable inhibitions over MAO-B, AChE, and BChE with IC<sub>50</sub> of 1.19–3.87 μM. A cell-based assay of compounds <b>2k</b> and <b>2n</b> against Vero normal cells pointed out their low cytotoxicity. In a docking simulation, <b>2k</b> showed the lowest energy for MAO-B (−11.6 kcal/mol) with four hydrogen bonds and two π-π interactions. Furthermore, in silico studies were conducted, and disclosed that <b>2k</b> and <b>2n</b> are expected to possess favorable pharmacokinetic properties, such as the ability to penetrate the blood–brain barrier (BBB). In view of these findings, compounds <b>2k</b> and <b>2n</b> could serve as promising potential candidates for the treatment of neurodegenerative diseases.
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