Zhang_2025_ChemistrySelect_10_e202500051

Abstract Fifteen new thiazole derivatives were synthesized and their cholinesterase inhibitory activities were evaluated. The design of these compounds involves linking thiazole rings to a cyclopropyl moiety, followed by substitutions with various amine groups. The structures of the synthesized thiazole-cyclopropyl compounds were confirmed using IR, HRMS, 1H-NMR, 13C-NMR, HPLC, and single-crystal X-ray diffraction. Compounds 6g and 6h were found to crystallize in a monoclinic system with space group P21/c, featuring alpha and ? angles of 90 degrees. Cholinesterase inhibition was assessed using the Ellman method. While most thiazole derivatives exhibited weak inhibitory effects on butyrylcholinesterase (BuChE), they showed significant inhibition of acetylcholinesterase (AChE). Compound 6l exhibited the most potent AChE inhibitory activity, with an IC50 of 0.079 +/- 0.16 microM, comparable to Donepezil (IC50 = 0.056 +/- 0.22 microM). Molecular docking, molecular dynamics simulations, and MM/GBSA binding free energy calculations confirmed stable interactions between compound 6l and the peripheral anionic site of AChE. Furthermore, metal ion chelation studies demonstrated that compound 6l, as a multitarget-directed ligand, effectively chelated biologically relevant metal ions. In summary, compound 6l shows significant potential as an AChE inhibitor and represents a promising lead compound for further research and development in Alzheimer's disease treatment.