Design, synthesis, molecular modeling, in vitro evaluation of novel piperidine-containing hydrazone derivatives as cholinesterase inhibitors.

Autor: Tok F; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, Istanbul, Türkiye., Baltaş N; Department of Chemistry, Faculty of Arts and Sciences, Recep Tayyip Erdoğan University, Rize, Türkiye., Abas Bİ; Department of Biochemistry, School of Medicine, Aydın Adnan Menderes University, Aydın, Türkiye., Tatar Yılmaz G; Department of Biostatistics and Medical Informatics, Faculty of Medicine, Karadeniz Technical University, Trabzon, Türkiye., Kaya S; Department of Biostatistics and Medical Informatics, Faculty of Medicine, Karadeniz Technical University, Trabzon, Türkiye., Koçyiğit-Kaymakçıoğlu B; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Biruni University, Istanbul, Türkiye., Çevik Ö; Department of Biochemistry, School of Medicine, Aydın Adnan Menderes University, Aydın, Türkiye.
Jazyk: angličtina
Zdroj: Drug development research [Drug Dev Res] 2024 Aug; Vol. 85 (5), pp. e22240.
DOI: 10.1002/ddr.22240
Abstrakt: 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 µM were obtained (IC 50  = 38.842 ± 0.053 µM 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 µM, respectively. In vitro, butyrylcholinesterase (BChE) inhibition values of the compounds were between 13.505 ± 0.025 and 52.230 ± 0.027 μm. Among the compounds, N6 has the highest BChE inhibition with an IC 50 value of 13.505 μm 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.
(© 2024 The Author(s). Drug Development Research published by Wiley Periodicals LLC.)
Databáze: MEDLINE
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