Novel (p-tolyl)-3(2H)-pyridazinone derivatives containing substituted-1,2,3-triazole moiety as new anti-Alzheimer agents: Synthesis, in vitro and in silico assays

Abstract

Alzheimer hastalığı (AH), demansın en yaygın nedeni olan kronik nörodejeneratif bir hastalıktır. Hastalığa yakalanma riski yaşla birlikte artar. Hastalığın histopatolojisi incelendiğinde senil amiloid plakları, nörofibriler yumak oluşumu, sinaps-nöron kaybı ve beyinde belirgin atrofi saptanır. Alzheimer hastalığında asetilkolin sentezinden sorumlu olan kolin asetil transferaz düzeyindeki azalma %58-90'dır. Mevcut ilaçlar hastalığın ilerlemesini durduramadığından, hastalığın temel nedenini hedef alan yeni ilaçlara büyük ihtiyaç vardır. Bu çalışmada asetilkolinesteraz inhibisyonu gösteren triazol-piridazinon türevi bileşikler sentezlenmiştir ve enzim inhibisyonları araştırılmıştır. Bileşik 6e, 0.049 ± 0.014 µM Ki değeri ile en güçlü inhibitör etkiyi göstermiştir (Takrin Ki= 0.226 ± 0.025 µM). Ayrıca sentezlenen tüm bileşikler için in-silico çalışmalar yapıldı.

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

“…The resulting mixture was poured into ice water, filtered off, and washed thoroughly with water. The resulting precipitate ( 3 ) was recrystallized from EtOH [25,26] …”

“…Molecular docking studies were applied to investigate the active binding modes of compound 6 a with PDB ID:4EY7, [37] compound 5 a interacting with PDB ID:4BDS [38] from the crystal structures obtained from the protein database. Ligands priming, receptor priming, and ligand-receptor in silico interaction were calculated following the procedure applied in previous studies [26,39,40] Possible conformations of the studied compounds were generated with the "Ligand preparation wizard" of Schrödinger 2021-2 LigPrep. [41] The crystal structure was prepared with the "Protein Preparation Wizard" of the Schrödinger 2021-2 Protein Preparation software.…”

“…[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] …”