Synthesis, biological evaluation and in silico studies of novel propargyl-tethered isatin hydrazones as monoamine oxidase inhibitors for Parkinson’s disease

= 1.96 ± 0.08 µM). Compound PSH18 showed the highest selectivity index value of 42.11, followed by PSH6 (22.35) and PSH2 (20.41). Additionally, PSH18 was confirmed to be a competitive and reversible inhibitor of MAO-B with an inhibition constant value of 0.89 ± 0.035 µM. Notably, PSH18 exhibited good permeability across the blood-brain barrier in parallel artificial membrane permeability assay experiments, along with acceptable absorption, distribution, metabolism, excretion, and toxicity parameters predicted through in silico modelling, suggesting its potential as a central nervous system-targeted molecule. Molecular docking and a 200 ns molecular dynamics simulation demonstrated stable binding of the ligand to the MAO-B active-site pocket, driven by hydrophobic and π-π stacking interactions with key amino acid residues lining the aromatic cage. Moreover, the calculated binding energy indicated strong ligand-protein interactions. Overall, these results indicate that the PSH scaffold could serve as a promising lead structure for the development of potent and selective MAO-B inhibitors. These compounds may have therapeutic potential for the treatment of neurodegenerative diseases.