Identification of New -methyl-piperazine Chalcones as Dual MAO-B/AChE Inhibitors.

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 -methyl-piperazine chalcones were synthesized, and their inhibitory activities were evaluated against the target enzymes. Compound (3-trifluoromethyl-4-fluorinated derivative) showed the highest selective inhibition against MAO-B with an IC of 0.71 μM and selectivity index (SI) of 56.34, followed by (2-fluoro-5-bromophenyl derivative) (IC = 1.11 μM, SI = 16.04). Compounds and were reversible competitive MAO-B inhibitors with K values of 0.21 and 0.28 μM, respectively. Moreover, and effectively inhibited AChE with IC of 8.10 and 4.32 μM, which underscored their multi-target inhibitory modes. Interestingly, compound elicited remarkable inhibitions over MAO-B, AChE, and BChE with IC of 1.19-3.87 μM. A cell-based assay of compounds and against Vero normal cells pointed out their low cytotoxicity. In a docking simulation, 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 and are expected to possess favorable pharmacokinetic properties, such as the ability to penetrate the blood-brain barrier (BBB). In view of these findings, compounds and could serve as promising potential candidates for the treatment of neurodegenerative diseases.