Makarian Makar, Gonzalez Michael, Salvador Stephanie M, Lorzadeh Shahrokh, Hudson Paula K, Pecic Stevan
Department of Chemistry & Biochemistry, California State University, Fullerton, USA.
Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0J9, Canada.
J Mol Struct. 2022 Jan 5;1247. doi: 10.1016/j.molstruc.2021.131425. Epub 2021 Sep 3.
In an effort to develop new therapeutic agents to treat Alzheimer's disease, a series of donepezil-based analogs were designed, synthesized using an environmentally friendly route, and biologically evaluated for their inhibitory activity against electric eel acetylcholinesterase (AChE) enzyme. studies revealed that the phenyl moiety of donepezil can be successfully replaced with a pyridine ring leading to equally potent inhibitors of electric eel AChE. Further kinetic evaluations of the most potent inhibitor showed a dual-binding (mixed inhibition) mode, similar to donepezil. Molecular modeling studies suggest that several additional residues could be involved in the binding of this inhibitor in the human AChE enzyme active site compared to donepezil.
为了开发治疗阿尔茨海默病的新型治疗药物，设计了一系列基于多奈哌齐的类似物，采用环境友好的路线进行合成，并对其抑制电鳗乙酰胆碱酯酶（AChE）的活性进行生物学评估。研究表明，多奈哌齐的苯基部分可以成功地被吡啶环取代，从而产生同样有效的电鳗AChE抑制剂。对最有效的抑制剂进行的进一步动力学评估显示出与多奈哌齐类似的双重结合（混合抑制）模式。分子模拟研究表明，与多奈哌齐相比，该抑制剂与人AChE酶活性位点结合时可能涉及几个额外的残基。
