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

Abstract

A 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 Nsubstituted-(p-chlorophenyl)pyridazin-3(2H)-one derivatives inhibited enzymes significantly. K i 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.

Hydrazide‐Bridged Pyridazines for Cholinesterase Inhibitors: Synthesis, Characterizations, In Silico, and In Vitro Evaluation

“…A comparison with the results of our group's previous study, especially regarding the activity of non-substituted derivatives (6 a), reveals a noteworthy consistency. However, the impact of substituents in the structures remains unclear, emphasizing the need for comparative studies in this regard (23).…”

“…Ethyl 2‐(2‐oxo‐5‐(phenylamino)pyridin‐1(2 H )‐yl)acetate ( 3 ) (1 equiv., 0.01 mmol) was dissolved in 25 mL of EtOH and hydrazine hydrate (3 mL) was added. The reaction medium was stirred at room temperature for 3 h. The precipitate formed was filtered, washed thoroughly with water, dried, and purified by crystallization from EtOH [23,24] …”

“…The reaction medium was stirred at room temperature for 3 h. The precipitate formed was filtered, washed thoroughly with water, dried, and purified by crystallization from EtOH. [23,24]…”

“…[22] Our previous studies explored the AChE inhibitory activities of synthesized pyridazin-3(2H)-one derivatives, revealing their significant enzyme inhibition. [23][24][25][26][27][28] Building on these findings, this study investigates the role of the linker by introducing acetohydrazide or benzenesulfonohydrazide groups to N-based heterocycle derivatives with a pyridazine moiety. These compounds, designed as dual binding site inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), demonstrate nanomolar-level inhibitory activity against these enzymes.…”

“…N‐based heterocycles, particularly pyridazine structures, have shown promise as anti‐cholinesterase agents [22] . Our previous studies explored the AChE inhibitory activities of synthesized pyridazin‐3(2H)‐one derivatives, revealing their significant enzyme inhibition [23–28] …”