Daud_2026_Chem.Biodivers_23_e71630

In this study, bis-Schiff base derivatives bearing 4-hydroxyacetophenone were synthesized and assessed for their in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities. In the series, compound (2i) was identified as the most promising inhibitor of AChE (IC(50) = 14.82 +/- 0.09 microM) and BuChE (IC(50) = 27.91 +/- 0.16 microM) enzymes surpassing the standard drug galantamine, while the remaining derivatives showed good to moderate inhibition. Structure-activity relationship (SAR) study exposed those methoxy groups attached to the benzene ring significantly improved enzyme inhibition, while electron-withdrawing groups led to condensed the activities. Molecular docking simulations against AChE and BuChE revealed distinct binding modes, with 2i forming critical bonds with catalytic residues. Quantum chemical analysis established strong correlations between electrophilicity index (omega = 4.712 eV for 2i), HOMO-LUMO gap (4.287 eV), and experimental inhibition. Quantum Theory of Atoms in Molecules (QTAIM) analysis supporting optimal electron density distribution and favorable non-covalent interaction patterns. Comprehensive in silico ADMET profiling predicted excellent pharmacokinetic properties for all derivatives, with 96%-100% human oral absorption, moderate blood-brain barrier (BBB) penetration for 2i, and low cardiac toxicity risk. The integrated computational-experimental approach provides supportive evidence for rational design of next-generation cholinesterase inhibitors with optimized efficacy and safety profiles.