Discovery of Novel Coumarin-Schiff Base Hybrids as Potential Acetylcholinesterase Inhibitors: Design, Synthesis, Enzyme Inhibition, and Computational Studies

To discover anti-acetylcholinesterase agents for the treatment of Alzheimer’s disease (AD), a series novel Schiff base-coumarin hybrids was rationally designed, synthesized successfully, and structurally characterized using Fourier transform infrared (FTIR), Nuclear magnetic resonance (NMR), High-Resolution Mass Spectrometry (HRMS) analyses. These were evaluated their potential inhibitory effect on acetylcholinesterase (AChE). All them exhibited excellent activity against AChE. The IC50 values ranged from 87.84 to 515.59 μg/mL; 13c 13d with 0.232 ± 0.011 0.190 0.004 µM, respectively, showed most potent as inhibitors (AChEIs). reference drug, Galantamine, yielded an 1.142 0.027 µM. Reactivity descriptors, including chemical (μ), hardness (η), electrophilicity (ω), condensed Fukui function, dual descriptors are calculated at wB97XD/6-311++ G (d,p) identify reactivity changes designed compounds. An in-depth investigation natural charge pattern studied compounds led deep understanding important interaction centers between these biological receptors molecular electrostatic surface (MESP) active site in derivatives determined high-quality information visualization. Molecular docking analysis performed predict binding sites energies. structure-activity-property relationship studies indicated that proposed exhibit good oral bioavailability properties. explore stability dynamic behavior ligand-receptor complexes, dynamics simulations (MDS) 100 ns two best docked derivatives, 13d, AChE (4EY7) receptor. A popular method determining free energies (MM/GBSA) is snapshots taken systems’ trajectories ns. results revealed complex system compound acquired relatively more stable conformation better than Galantamine suggesting its effective inhibiting drug. energy 13d-4EY7 greater compared other complexes.