Morpholine-Based Chalcones as Potent and Selective MAO-B Inhibitors With Preliminary CNS Drug-Like Properties

A series of morpholine-based chalcone derivatives containing alkoxy substituents was designed and synthesized using a rapid and environmentally friendly microwave-assisted protocol. The synthesized compounds were fully characterised by NMR, FTIR, and HRMS analyses and evaluated in vitro against primarily monoamine oxidases, as well as acetylcholinesterase, butyrylcholinesterase, and β-site amyloid precursor protein cleaving enzyme 1, which are closely associated with neurodegenerative disorders. Although most compounds showed weak inhibition of AChE, BChE, and BACE1, they exhibited potent and selective MAO-B inhibitory activity. Among them, MBC21 emerged as the most potent MAO-B inhibitor (IC₅₀ = 0.069 ± 0.0075 μM; SI 243.33), acting as a competitive and reversible inhibitor. In addition, MBC1, MBC2, and MBC24 displayed notable BChE inhibitory activity, while MBC24 demonstrated multi-target activity against MAO-B, AChE, and BChE. Molecular docking and molecular dynamics simulations revealed that the selectivity of MBC21 towards hMAO-B is associated with stable hydrophobic interactions and π-π stacking with TYR326. Furthermore, in silico ADME prediction, microsomal stability, and PAMPA-BBB studies demonstrated favorable drug-like properties, improved metabolic stability, and moderate brain permeability for MBC21. Taken together, these findings identify MBCs, particularly MBC21, as promising lead candidates for the development of selective MAO-B inhibitors for neurodegenerative disease therapy.