Novel Benzoxazole Derivatives as Potential Acetylcholinesterase (AChE) Inhibitors in Alzheimer's Disease: Molecular Docking and Pharmacokinetics Analysis

ABSTRACT Alzheimer's disease (AD) is a neurodegenerative disease whose leading cause is multiple brain abnormalities caused by the aging process. One key pathological mechanism of AD is the dysfunction of acetylcholine due to its breakdown by the acetylcholinesterase (AChE) enzyme. Although several synthetic AChE inhibitors such as donepezil exist, they often cause adverse side effects and are costly. In this study, six new benzoxazole derivatives ( F1‐6 ) were synthesized and characterized using FT‐IR and 1 H‐NMR. Benzoxazole derivatives have shown potential neuroprotective effects, including cognitive improvement and amyloid‐β reduction. To evaluate benzoxazole and its six derivatives as potential AChE inhibitors through in silico analysis. Molecular docking studies revealed that the effectiveness of compounds ( F1‐6 ) is comparable with that of Donepezil, an FDA‐approved anti‐Alzheimer drug against acetylcholinesterase (AChE) enzyme, responsible for many side effects. The interaction of the F3 compound with protein 4EY7 causes the most negative binding energy (‐7.663 kcal/mol), while the calculated value for the Donepezil compound is (−8.695 kcal/mol). Other compounds ( F4 , F5 , and F6 ) show a good binding energy for 4EY7 (−6.562, −6.420, and −6.375 kcal/mol, respectively). Pharmacokinetics and toxicity analysis also revealed good candidacy of these compounds, may therefore be recommended as new anti‐Alzheimer agents to contrast acetylcholinesterase (AChE) enzyme.