Design, Synthesis, and Assay of New N-acyl-4-(4-aminoalkoxy- phenyl)- thiazole-2-amine Derivatives as Acetylcholinesterase Inhibitors

Abstract

Background: Thiazoles are an important class of heterocyclic compounds with many biological effects, including anticholinesterase activity. Objective: The purpose of this work was to synthesize new thiazole derivatives and evaluate as acetylcholinesterase inhibitors (AChEIs) for Alzheimer’s disease. Methods: A series of new N-acyl-4-(4-aminoalkoxy-phenyl)-thiazole-2-amine derivatives was designed and synthesized. Ellman assay protocol was used for the AchE and BuChE inhibitory activity. To correlate better the drug-like property, the theoretical prediction was calculated using Mol inspiration software 2015 online. The potential binding mode of compounds with AChE and BuChE was investigated by the molecular docking simulation. Results: All synthesized compounds exhibited a certain inhibitory activity on AChE and 5p had the most effective selective inhibitory effect on AChE. The inhibitory form of 5p on AChE was shown to be a combination of competitive and noncompetitive inhibition, according to enzyme kinetic tests. Docking simulation studies revealed that the binding energy of 5p with AChE was lower than that of it with BuChE, which also explained the selective inhibitory activity of 5p on AChE. Conclusion: These results provided valuable information for the design of potent AChEIs, and it was believed that 5p could be a promising lead structure for its further development for the treatment of AD.