Alzheimer's disease (AD) is a progressive neurodegenerative disease with known original cholinergic dysfunction and decreased acetylcholine levels in the brain. Acetylcholinesterase (AChE) remains a validated therapeutic target for the symptomatic management of AD; however, currently available inhibitors suffer from limitations such as adverse effects and limited efficacy. Hence, alternative development of new AChE inhibitors with better pharmacological properties. In this research, a rational, thinkable series of ten novel pyrrolidine derivatives (A1-A10) was designed and confirmed by using a combined in silico approach. ChemDraw Ultra 22.2.0 and Chem3D 22.2.0 were used to design and optimize the ligands, and proprietary molecular docking programs of ArgusLab 4.0.1 were then used to dock the designed molecules with the human acetylcholinesterase (PDB ID: 4EY7). Moreover, drug-likeness, pharmacokinetic, and toxicity properties have been predicted with Swiss ADME and ProTox-II. Molecular docking results showed that the compounds A9, A3, and A2 had better docking scores as -14.3587, -13.7695, and -13.3849 kcal/mol, respectively, compared to donepezil (-13.0325 kcal/mol). Such compounds showed good interactions in the catalytic gorge of the AChE. The physicochemical properties, gastrointestinal absorption, blood – brain barrier penetration, and CNS permeability were adequate with favorable results seen during ADMET evaluation, and the toxicity was predicted to be low. In conclusion, the results indicated that pyrrolidine derivatives, notably A9, A3, and A2, appear to be good starting points for creating novel anti-Alzheimer drugs acting as inhibitors of acetylcholinesterase and should be thoroughly examined in experimental validation.
Publication Date: 2026-06-19