Design, synthesis, biological evaluation, and in silico studies of cholinesterase inhibitors based on the 2-aminothiazole scaffold

In this study, a series of 2-aminothiazole derivatives were designed, synthesized, and evaluated as potential cholinesterase inhibitors (ChEIs) for the treatment of Alzheimer’s disease (AD). Subsequently, the antioxidant activities of these synthesized compounds were assessed using the DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging assay. The results of the cholinesterase (ChE) inhibition assays revealed that most of the compounds exhibited certain inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among them, compound 14s demonstrated the most potent inhibitory activity against AChE, with IC₅₀ value of 3.54 μM. Meanwhile, compound 14s also exhibited moderate inhibitory activity against BuChE, with IC₅₀ value of 7.95 μM. The inhibitory activities of compound 14s against both AChE and BuChE were superior to those of galantamine (AChE: IC₅₀ = 3.47 μM; BuChE: IC₅₀ = 17.31 μM). The type of inhibition for compound 14s was determined through enzyme kinetic studies, and the results showed that the compound was a mixed type inhibitor. In addition, molecular docking results showed that compound 14s could interact with the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE, which was consistent with the enzyme kinetic experimental results. Molecular dynamics (MD) simulation studies demonstrated the stability of the 14s-AChE/BuChE complexes. Moreover, results from the DPPH free radical scavenging assay indicated that the compounds also exhibited antioxidant activity. Collectively, these experimental results indicated that the designed and synthesized ChEI 14s exhibits potential for further research.