The cholinergic hypothesis is one of the basic approaches for designing and discovering novel anti-Alzheimer drugs. Application of the pharmacophore of well-known drugs like donepezil helps us achieve new molecules. In the current project, a new series of benzamide derivatives () were designed and synthesized. Spectroscopic techniques (NMR, IR, MS) were utilized for characterization. Subsequently, Ellman’s protocol was carried out for acetylcholinesterase assay and the obtained results were compared to donepezil (IC = 0.6 ± 0.05 µM). Compound which bears a chlorine atom at position of the phenyl ring was the most potent derivative in this series (IC = 0.14 ± 0.03 nM) and exhibited higher activity than donepezil. In addition, molecular docking was performed to explore the binding mode and related interactions. The results demonstrated that compound binds to the active site of the AChE through a hydrogen bond with Trp279. This compound could be suggested as a potential lead compound and more experimental and tests are needed to prove its eligibility as a drug candidate.

中文翻译：

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新型乙酰胆碱酯酶抑制剂：4-苯甲酰胺基-N-(1-苄基哌啶-4-基)苯甲酰胺衍生物的合成、对接及抑制活性评价


胆碱能假说是设计和发现新型抗阿尔茨海默病药物的基本方法之一。应用多奈哌齐等知名药物的药效团可以帮助我们获得新的分子。在当前的项目中，设计并合成了一系列新的苯甲酰胺衍生物()。利用光谱技术（NMR、IR、MS）进行表征。随后，按照 Ellman 方案进行乙酰胆碱酯酶测定，并将所得结果与多奈哌齐进行比较 (IC = 0.6 ± 0.05 µM)。在苯环位置带有氯原子的化合物是该系列中最有效的衍生物 (IC = 0.14 ± 0.03 nM)，并且表现出比多奈哌齐更高的活性。此外，还进行了分子对接来探索结合模式和相关相互作用。结果表明，该化合物通过与 Trp279 的氢键与 AChE 的活性位点结合。该化合物可以被建议作为潜在的先导化合物，并且需要更多的实验和测试来证明其作为候选药物的资格。