Halogenated Coumarin–Chalcones as Multifunctional Monoamine Oxidase-B and Butyrylcholinesterase Inhibitors

[Image: see text] A series of halogenated coumarin–chalcones were synthesized, characterized, and their inhibitory activities against monoamine oxidases (MAOs), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein cleaving enzyme 1 (BACE-1) were evaluated. Compound CC2 most potently inhibited MAO-B with an IC(50) value of 0.51 μM, followed by CC1 (IC(50) = 0.69 μM), with a selectivity index (SI) of >78.4 and >58.0, respectively, over MAO-A. However, none of the compounds effectively inhibited MAO-A, AChE, and BChE, except for CC2 and CC3 inhibiting BChE with IC(50) values of 7.00 (SI > 5.73 over AChE) and 11.8 μM, respectively. CC1 and CC2 were found to be reversible and competitive inhibitors of MAO-B, with K(i) values of 0.50 ± 0.06 and 0.53 ± 0.04 μM, respectively, and CC2 was also a reversible and competitive inhibitor of BChE, with a K(i) value of 2.84 ± 0.09 μM. The parallel artificial membrane permeability assay (PAMPA) method showed that lead candidates can cross the blood–brain barrier (BBB). The in vitro toxicity analysis on the Vero cell line (Normal African green monkey kidney epithelial cells) by MTT confirmed that both CC1 and CC2 were nontoxic up to 100 μg/mL, which is almost equivalent to 100 times of their effective concentration used in biological studies. In addition, CC1 and CC2 attenuated H(2)O(2)-induced cellular damage via their reactive oxygen species (ROS) scavenging effect. These results suggest that CC1 and CC2 are selective and competitive inhibitors of MAO-B, and that CC2 is a selective and competitive inhibitor of BChE. Molecular docking studies of lead compounds provided the possible type of interactions in the targeted enzymes. Based on the findings, both compounds, CC1 and CC2, can be considered plausible drug candidates against neurodegenerative disorders.