Tok_2024_Drug.Dev.Res_85_e22240

In an effort to develop new and effective therapeutic agents for Alzheimer's disease, a series of hydrazone derivatives bearing piperidine rings have been designed and synthesized. The chemical structures of the compounds were characterized by various spectroscopic techniques. In vitro antioxidant and cholinesterase activities of the compounds were evaluated. Among the compounds, N12 exhibited the most antioxidant activity in all methods (CUPRAC, FRAP, DPPH, ABTS). In vitro acetylcholinesterase (AChE) activity results of the compounds showed good IC(50) values between 14.124 +/- 0.084 and 49.680 +/- 0.110 microM were obtained (IC(50) = 38.842 +/- 0.053 microM for Donepezil). Among the compounds, N7 and N6 are much more effective derivatives than the standard compound donepezil with IC(50) values of 14.124 +/- 0.084 and 17.968 +/- 0.072 microM, respectively. In vitro, butyrylcholinesterase (BChE) inhibition values of the compounds were between 13.505 +/- 0.025 and 52.230 +/- 0.027 microm. Among the compounds, N6 has the highest BChE inhibition with an IC(50) value of 13.505 microm in the series. The cytotoxicity and AChE inhibitory activity of the compounds on SH-SY5Y cell lines were also evaluated. Kinetic studies were also performed to determine the behavior of the compounds as competitive or noncompetitive inhibitors. The binding modes of N6, which was determined to be highly effective according to in vitro analyses, with AChE and BChE were investigated using molecular docking studies, and the stability of the complexes was determined by molecular dynamics simulations. These findings indicated that AChE and BChE enzymes maintained their overall structural stability and compactness during interactions with compound N6.