<i>In Vitro</i> Biological Screening and In Silico Molecular Modeling Studies of Thiadiazole-Bearing Benzoxazole Derivatives as Promising Acetylcholinesterase and Butyrylcholinesterase Inhibitors

This research focuses on the design, synthesis and biological evaluation of imidazopyridine-based thiadiazole derivatives incorporating benzoxazole moieties. These compounds were investigated as dual inhibitors of acetylcholinesterase (AChE) and butyrylcholineesterase (BuChE), crucial for neurotransmission. Targeting these enzymes presents a viable strategy for controlling neurological conditions, particularly Alzheimer’s disease (AD). A total of 18 derivatives (1–18) were synthesized and structurally characterized using 1 H NMR, [Formula: see text]C NMR and HREI-MS techniques. The in vitro enzyme inhibition assays demonstrated significant activity, with IC[Formula: see text] values ranging from 1.10 ± 0.70 [Formula: see text]M to 35.80 ± 7.60 [Formula: see text]M for AChE and 2.40 ± 0.90 [Formula: see text]M to 37.50 ± 7.80 [Formula: see text]M for BuChE. In comparison, the reference drug Donepezil exhibited IC50 values of 10.30 ± 1.10 [Formula: see text]M and 15.60 ± 1.80 [Formula: see text]M for AChE and BuChE, respectively. Derivatives 14, 10, 4 and 9 showed the strongest inhibitory effects among the synthesized compounds. Furthermore, molecular docking studies were performed to elucidate the interaction of these derivatives with the active sites of AChE and BuChE. The computational findings aligned with the experimental data, confirming strong binding affinities and favorable interaction profiles. These findings underscore the therapeutic potential of these compounds as potential anti-AChE and BuChE agents, particularly in the context of Alzheimer’s disease treatment.