Abstract
•A dual series of bromo- and fluoro-based α,β-unsaturated ketones were prepared and characterized.•CHB3 and CHF3 were potent MAO-B inhibitors with IC50 values of 0.0062 and 0.011 µM, respectively.•CHB3 and CHF3 were reversible competitive inhibitors of MAO-B.•The molecular interactions of CHB3 and MAO-B were studied by molecular docking and dynamics.•CHB3 can be a candidate therapeutic agent for neurological disorders, such as Parkinson's disease.
This study evaluated the synthesis of a dual series of bromo (CHB1–CHB4)- and fluoro (CHF1–CHF4)-based α,β-unsaturated ketones and their inhibitory activities against monoamine oxidase (MAO)-A and MAO-B. All compounds exhibited potent MAO-B inhibitory activities compared with the reference drugs. Among the CHB derivatives, CHB3 exhibited the highest potent inhibitory activity against MAO-B, with an IC50 value of 0.0062 µM, followed by CHB2 (IC50 = 0.013 µM), CHB4 (IC50 = 0.023 µM), and CHB1 (parent compound in the subseries, IC50 = 0.027 µM). Among the CHF derivatives, CHF3 demonstrated an efficient inhibitory activity against MAO-B, with an IC50 value of 0.011 µM, followed by CHF2 (IC50 = 0.037 µM), CHF1 (IC50 = 0.042 µM; parent compound in the subseries), and CHF4 (IC50 = 0.160 µM). CHB3 and CHF3 were found to be reversible competitive inhibitors of MAO-B, with Ki values of 0.0078 ± 0.0010 and 0.0068 ± 0.0012 µM, respectively. To confirm the promising action of CHB3, which is the most potent compound, the molecular basis of its interaction to MAO-B was studied by molecular docking and dynamics. The results suggested that CHB3 is a candidate therapeutic agent against neurological disorders, such as Parkinson's disease.
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