| Summary: | Nineteen tosylated acyl hydrazone derivatives were synthesized, and their inhibitory activities against monoamine oxidases (MAOs), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-secretase (BACE-1) were evaluated. Compound <b>3o</b> was the most potent inhibitor of MAO-A, with an IC<sub>50</sub> value of 1.54 µM, followed by <b>3a</b> (IC<sub>50</sub> = 3.35 µM). A structural comparison with <b>3a</b> indicated that the 3-F group in <b>3o</b> increased its inhibitory activity against MAO-A. Compound <b>3s</b> was the most potent inhibitor of MAO-B, with an IC<sub>50</sub> value of 3.64 µM, followed by <b>3t</b> (IC<sub>50</sub> = 5.69 µM). The MAO-B inhibitory activity increased in the order of 3- > 4- > 2-NO<sub>2</sub> groups in <b>3s</b>, <b>3t</b>, and <b>3r</b>, respectively. All the compounds weakly inhibited AChE and BChE, which retained >50% residual activity at 10 µM, except for <b>3a</b>, which inhibited BChE with an IC<sub>50</sub> value of 16.1 µM. Interestingly, <b>3e</b>, <b>3f</b>, and <b>3n</b> inhibited BACE-1 with IC<sub>50</sub> values of 8.63, 9.92, and 8.47 µM, respectively, which were lower than the IC<sub>50</sub> of the quercetin reference. Compounds <b>3o</b> and <b>3s</b> were found to be reversible competitive inhibitors of MAO-A and MAO-B, respectively, with K<sub>i</sub> values of 0.35 ± 0.074 and 1.97 ± 0.65 µM, respectively. Moreover, compounds <b>3e</b>, <b>3f</b>, and <b>3n</b> were effective BACE-1 inhibitors. The lead molecules were further investigated by molecular docking studies to elucidate the binding interactions with the target enzymes.
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