Synthesis and Molecular Docking Studies of New Ibuprofen Derivatives as AChE, BChE, and COX-2 Inhibitors

Abstract

Alzheimer's disease (AD), the most common age-related neurodegenerative condition, is named after Alois Alzheimer and is marked by a progressive deterioration in memory, cognitive function, and behavior. Research has highlighted the importance of nonsteroidal anti-inflammatory drugs (NSAIDs) in inhibiting the aggregation of amyloid β-peptide (Aβ), a key feature of AD pathology. Ibuprofen, an NSAID from the propionic acid class, is widely used to manage osteoarthritis and rheumatoid arthritis, exhibiting strong anti-inflammatory and antipyretic effects. However, the drug's acidic group limits its selectivity for cyclooxygenase (COX) enzymes and contributes to several adverse effects. This study aimed to modify the acidic moiety of ibuprofen into lactone (IBU-O 1–4) and lactam (IBU-I 1–3) derivatives to mitigate these side effects. The structural properties of the synthesized imidazolone (IBU-I 1–3) and oxazolone (IBU-O 1–4) derivatives were characterized through Q-TOF LC-MS, ¹H-NMR, ¹3C-NMR, and IR spectroscopy. Molecular docking studies followed by Ellman's method assessed the inhibitory effects of these compounds on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), while an enzyme immunoassay (EIA) kit was used to evaluate their inhibition of cyclooxygenase-2 (COX-2).