Rational Design and In Silico Evaluation of Benzimidazole-Fused Pyran Derivatives as Acetylcholinesterase Inhibitors for Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by cholinergic dysfunction, for which acetylcholinesterase (AChE) inhibition remains a clinically validated symptomatic treatment strategy. In the present study, a series of benzimidazole-dihydropyran hybrid derivatives ( 4a-n ) were rationally designed and evaluated using an integrated computational workflow to identify promising AChE inhibitors. Molecular docking demonstrated favorable binding of several derivatives within both the catalytic active site and peripheral anionic site of AChE, stabilized by π-π stacking, hydrogen bonding, and hydrophobic interactions with key residues. ADMET profiling predicted acceptable oral bioavailability, blood-brain barrier permeability, and drug-like properties for the prioritized compounds. Density functional theory analysis revealed that the most active candidates possessed narrow HOMO-LUMO energy gaps, indicating enhanced electronic complementarity and charge-transfer capability within the AChE binding gorge. Machine learning-assisted QSAR modeling further supported the activity trends and highlighted compounds 4b, 4c, 4f , and 4i as the most promising leads. These results establish the benzimidazole-dihydropyran scaffold as a viable platform for the development of next-generation AChE inhibitors and provide a robust computational basis for subsequent experimental validation toward Alzheimer’s disease therapy.