Targeting AChE and BChE enzymes with novel chalcone-based hybrid compounds containing imidazo[2,1-b][1,3,4]thiadiazole group: An integrated synthesis, characterization, in silico and in vitro study

Abstract

In this study, a series of novel chalcone derivatives bearing an imidazothiadiazole group were synthesized and since they are approved targets in the treatment of Alzheimer's disease, their inhibitory potentials against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were investigated by in silico methods and in vitro experiments. In the initial stage, the syntheses of the compounds were carried out, and the structures of the compounds were confirmed by 1H NMR, 13C NMR, FT-IR and MS and elemental analysis. Subsequently, the AChE and BChE inhibition potentials of these compounds were investigated by in silico techniques, including molecular docking, molecular dynamics simulations and binding free energy calculations. Molecular dynamics simulations and binding free energy calculations suggested that the compounds may have significant potential as AChE and BChE inhibitors. Therefore, in vitro enzyme inhibition assays were also performed, and the results were compared with the reference drugs donepezil and tacrine. It was found that the synthesized compounds have K<inf>i</inf> values in the range of 13.45±5.07 – 102.78±28.04 nM for AChE and 15.34±6.03 – 116.01±18.76 nM for BChE, while tacrine and donepezil have K<inf>i</inf> values of 123.41±16.50 and 87.92±4.12 nM for AChE, and 89.44±16.81 and 73.85±6.02 nM for BChE, respectively, showing that the synthesized compounds could be effective AChE and BChE inhibitors. © 2025 Elsevier B.V., All rights reserved.