(p‐Chlorophenyl)‐3(2H)pyridazinone Derivatives: Synthesis, in Silico, and AChE/BChE Inhibitory Activity

Abstract

AbstractA series of novel (p‐chlorophenyl)‐3(2H)pyridazinone compounds were synthesized starting from p‐chloroacetophenone as AChE/BChE inhibitors. The chemical structures of all the compounds were identified by spectral analysis. Cholinesterase inhibition activity studies and in silico studies of compounds designed to eliminate the symptomatic effects of Alzheimer's disease and slow down neurodegeneration were evaluated. According to the results obtained, it was revealed that N‐substituted‐(p‐ chlorophenyl)pyridazin‐3(2H)‐one derivatives inhibited enzymes significantly. Ki values were found for acetylcholinesterase in the range of 10.2±4.0–20.9±7.6 nM and for butyrylcholinesterase in the range of 0.70±0.34–1.67±1.12 nM. Compound 5e showed the best effect on AChE activity compared to Tacrine. Also, compound 5b showed the best effect in BChE inhibition. The interactions of the synthesized compounds with the best experimental activities against AChE, BChE, respectively, were investigated by in silico approaches. In molecular docking, 5b compound with AChE crystal structure (PDB ID:1ACJ), binding site and binding parameters of 5e compound with BChE crystal structure were investigated in detail. The results indicated that compound 5b and 5e could be a promising lead compound for further development as a therapeutic agent for Alzheimer's disease.