Development of 1-(substituted benzofuran-2-yl)-3-(halogen-substituted phenyl)prop-2-en-1-ones as potent, reversible, and selective MAO-B inhibitors for Parkinson's Disease.

Ten halogenated benzofuran derivatives (BF1-BF10) were synthesized and evaluated for their inhibitory activity against monoamine oxidase isoforms. All compounds showed stronger inhibition of MAO-B compared to MAO-A. Among them, BF2 exhibited the most potent MAO-B inhibition (IC₅₀ = 0.082 µM), followed by BF5 (IC₅₀ = 0.095 µM) and BF1 (IC₅₀ = 0.16 µM), with high selectivity indices, particularly BF2 (SI = 1038.05). Kinetic studies revealed that BF2 acts as a competitive inhibitor with a Ki value of 0.083 ± 0.0056 µM. Dialysis experiments confirmed its reversible inhibition profile, comparable to the reference drug Safinamide. Both BF2and BF5 were non-cytotoxic toward L929 cells and demonstrated moderate blood-brain barrier permeability in PAMPA assay. Molecular docking showed stabilization of MAO-B via π-π stacking interactions with Tyr326 and Tyr398, and molecular dynamics simulations further confirmed stable binding of BF2 within the MAO-B active site. Overall, BF2 emerged as a potent, selective, and reversible MAO-B inhibitor, warranting for further investigation.