Shah_2026_Future.Med.Chem__1

AIMS: To design, synthesize, and evaluate novel imidazo[1,2-a]pyridine derivatives as dual acetylcholinesterase (AChE) and beta-secretase (BACE1) inhibitors for potential Alzheimer's disease (AD) therapy. MATERIALS AND METHODS: A series of imidazo[1,2-a]pyridine derivatives (DS1-DS15) were synthesized via cyclization using various aryl and heteroaryl acids and characterized by MP, TLC, FTIR, MS, and (1)H/(13)C NMR spectroscopy. Molecular docking studies were performed against AChE (PDB ID: 4EY7) and BACE1 (PDB ID: 4ACU). Pharmacokinetic properties were predicted using pkCSM, and molecular dynamics simulations were conducted for the lead compound. In vitro inhibitory activities were determined by IC(5)(0) values. In vivo anti-AD activity was evaluated in male Sprague Dawley rats using biochemical assays and histological analysis. RESULTS: Compound DS7 showed the highest binding affinity toward both targets with stable protein-ligand interactions. It exhibited potent AChE inhibition (IC(5)(0) = 0.054 microM) and significant BACE1 inhibition (IC(5)(0) = 5.67 microM). In vivo studies demonstrated significant reversal of AD-associated biochemical and histopathological alterations at high dose. CONCLUSION: DS7 emerged as a promising dual AChE/BACE1 inhibitor and a potential lead candidate for further optimization in AD drug development.