Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, Eskişehir, Turkey.
Department of Chemistry, Faculty of Science, Eskisehir Technical University, Eskişehir, Turkey.
Arch Pharm (Weinheim). 2024 Oct;357(10):e2400067. doi: 10.1002/ardp.202400067. Epub 2024 Jul 5.
The development of targeted phthalazine-1,4-dione acetylcholinesterase (AChE) inhibitors for treating Alzheimer's disease involved the synthesis of 32 compounds via a multistage process. Various analytical techniques confirmed the compounds' identities. Thirteen compounds were found to inhibit AChE by more than 50% without affecting butyrylcholinesterase (BChE). Among these, three compounds, 8m, 8n, and 8p, exhibited extraordinary activity similar to donepezil, a reference AChE inhibitor. During enzyme kinetic studies, compound 8n, displaying the highest AChE inhibitory activity, underwent evaluation at three concentrations (2 × IC, IC, and IC/2). Lineweaver-Burk plots indicated mixed inhibition activity for compound 8n against AChE, suggesting a combination of competitive and noncompetitive characteristics. Additionally, effective derivatives 8m, 8n, and 8p exhibited high blood-brain barrier (BBB) permeability in in vitro parallel artificial membrane permeability assay tests. Molecular docking studies revealed that these compounds bind to the enzyme's active site residues in a position similar to donepezil. Molecular dynamic simulations confirmed the stability of the protein-ligand system, and the chemical reactivity characteristics of the compounds were investigated using density functional theory. The compounds' wide energy gaps suggest stability and therapeutic potential. This research represents a significant step toward finding a potential cure for Alzheimer's disease. However, further research and testing are required to determine the compounds' safety and efficacy. The unique structure of phthalazine derivatives makes them suitable for various biological activities, and these compounds show promise for developing effective drugs for treating Alzheimer's disease. Overall, the development of these targeted compounds is a crucial advancement in the search for an effective treatment for Alzheimer's disease.
为了治疗阿尔茨海默病，开发靶向邻苯二甲酰亚胺-1,4-二酮乙酰胆碱酯酶（AChE）抑制剂涉及通过多步过程合成 32 种化合物。各种分析技术证实了这些化合物的身份。发现 13 种化合物可抑制 AChE 超过 50%，而不影响丁酰胆碱酯酶（BChE）。在这些化合物中，三种化合物 8m、8n 和 8p 表现出与参考 AChE 抑制剂多奈哌齐相似的非凡活性。在酶动力学研究中，显示出最高 AChE 抑制活性的化合物 8n 在三个浓度（2×IC、IC 和 IC/2）下进行了评估。Lineweaver-Burk 图谱表明化合物 8n 对 AChE 具有混合抑制活性，表明其具有竞争性和非竞争性特征的结合。此外，有效衍生物 8m、8n 和 8p 在体外平行人工膜渗透率测定试验中表现出较高的血脑屏障（BBB）渗透率。分子对接研究表明，这些化合物与酶的活性部位残基结合的位置与多奈哌齐相似。分子动力学模拟证实了蛋白质-配体系统的稳定性，并用密度泛函理论研究了化合物的化学反应性特征。这些化合物的宽能隙表明其稳定性和治疗潜力。这项研究是寻找阿尔茨海默病潜在治疗方法的重要一步。然而，需要进一步的研究和测试来确定这些化合物的安全性和疗效。邻苯二甲酰亚胺衍生物的独特结构使它们适合各种生物活性，并且这些化合物有望开发出治疗阿尔茨海默病的有效药物。总体而言，这些靶向化合物的开发是寻找阿尔茨海默病有效治疗方法的关键进展。
