Development of morpholine ring-bearing halogenated α,β-unsaturated ketones as selective monoamine oxidase-B inhibitors

다국어 초록 (Multilingual Abstract)

Nine morpholine-derived halogenated chalcone derivatives (MHC1-MHC9) were synthesized, and their inhibitory activity against monoamine oxidase (MAO) was evaluated. MHC5 showed the highest inhibitory activity against MAO-B with an IC50 value of 0.065 μM, followed by MHC7 (IC50=0.078 μM) and MHC6 (IC50=0.082 μM).
The para-F substituent MHC4 was also potent (IC50=0.095 μM). The selectivity index values of all the compounds were high for MAO-B over MAO-A, and the values for MHC5 and MHC4 were 66.15 and 80.11, respectively. MHC5 and MHC4 were competitive MAO-B inhibitors with Ki values of 0.024±0.00062 and 0.041±0.0028 μM, respectively.
In reversibility tests, the changes in residual activity before and after the dialysis of MHC5 and MHC4 were similar to those of safnamide, a reversible MAO-B reference inhibitor. Additionally, molecular docking and dynamic simulations predicted that the lead molecules MHC5 and MHC4 could strongly bind to the MAO-B active site with docking scores of –10.92±0.08 and –10.64±0.14 kcal/mol, respectively. Additionally, MHC4 and MHC5 exhibited favorable ADME features, including blood–brain barrier permeability. The experiments confrmed that MHC5 and MHC4 are reversible and potent selective inhibitors of MAO-B and are promising candidates for the treatment of neurodegenerative diseases (human health).