Development of bromo- and fluoro-based α, β-unsaturated ketones as highly potent MAO-B inhibitors for the treatment of Parkinson's disease

This study evaluated the synthesis of a dual series of bromo (CHB1-CHB4)-and fluoro (CHF1-CHF4)-based alpha,beta-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 mu M, followed by CHB2 (IC50 = 0.013 mu M), CHB4 (IC50 = 0.023 mu M), and CHB1 (parent compound in the subseries, IC50 = 0.027 mu M). Among the CHF derivatives, CHF3 demonstrated an efficient inhibitory activity against MAO-B, with an IC50 value of 0.011 mu M, followed by CHF2 (IC50 = 0.037 mu M), CHF1 (IC50 = 0.042 mu M; parent compound in the subseries), and CHF4 (IC50 = 0.160 mu M). 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 mu M, 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. (C) 2022 Elsevier B.V. All rights reserved.

Automated summary

This study evaluated the inhibitory activities of a series of alpha,beta-unsaturated ketone compounds against MAO-A and MAO-B. CHB3 and CHF3 showed the most potent inhibitory activity against MAO-B and were identified as reversible competitive inhibitors. CHB3 was considered a potential candidate for treating neurological disorders such as Parkinson's disease.