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

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 most potently inhibited MAO-B with an IC value of 0.51 μM, followed by (IC = 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 and inhibiting BChE with IC values of 7.00 (SI > 5.73 over AChE) and 11.8 μM, respectively. and were found to be reversible and competitive inhibitors of MAO-B, with values of 0.50 ± 0.06 and 0.53 ± 0.04 μM, respectively, and was also a reversible and competitive inhibitor of BChE, with a 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 toxicity analysis on the Vero cell line (Normal African green monkey kidney epithelial cells) by MTT confirmed that both and were nontoxic up to 100 μg/mL, which is almost equivalent to 100 times of their effective concentration used in biological studies. In addition, and attenuated HO-induced cellular damage via their reactive oxygen species (ROS) scavenging effect. These results suggest that and are selective and competitive inhibitors of MAO-B, and that 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, and , can be considered plausible drug candidates against neurodegenerative disorders.