Background: Benzimidazole is an interesting pharmacophore which has been extensively studied in medicinal chemistry due to its high affinity towards various enzymes and receptors. Its derivatives have been previously shown to possess a wide range of biological activities including anthelmintic, antihypertensive, antiulcer, as well as anticholinesterase activity.

Objective: The objective of this study is to search for more potent benzimidazole-based cholinesterase inhibitors, through the modification of the 1- and 2-positions of the benzimidazole core.

Methods: Synthesis of compounds were carried out via a 4-step reaction scheme following a previously reported protocol. Structure-activity relationship of the compounds are established through in vitro cholinesterase assays and in silico docking studies. Furthermore, cytotoxicity and blood brain barrier (BBB) permeability of the compounds were also investigated.

Results: Among the synthesised compounds, three of them (5IIa, 5IIb, and 5IIc) exhibited potent selective butyrylcholinesterase inhibition at low micromolar level. The compounds did not show any significant cytotoxicity when tested against a panel of human cell lines. Moreover, the most active compound, 5IIc, was highly permeable across the blood brain barrier.

Conclusion: In total 10 benzimidazole derivatives were synthesized and screened for their AChE and BuChE inhibitory activities. Lead compound 5Iic, represents a valuable compound for further development as potential AD therapeutics.

背景：苯并咪唑是一种有趣的药效团，由于其对各种酶和受体的高亲和力，在药物化学中得到了广泛的研究。其衍生物先前已被证明具有广泛的生物活性，包括驱虫、抗高血压、抗溃疡以及抗胆碱酯酶活性。

目的：本研究的目的是通过修饰苯并咪唑核心的 1- 和 2- 位，寻找更有效的苯并咪唑类胆碱酯酶抑制剂。

方法：根据先前报道的方案，通过 4 步反应方案进行化合物的合成。化合物的构效关系是通过体外胆碱酯酶测定和计算机对接研究建立的。此外，还研究了化合物的细胞毒性和血脑屏障 (BBB) 渗透性。

结果：在合成的化合物中，其中三种（5IIa、5IIb 和 5IIc）在低微摩尔水平下表现出有效的选择性丁酰胆碱酯酶抑制作用。当针对一组人类细胞系进行测试时，这些化合物没有表现出任何显着的细胞毒性。此外，最活跃的化合物 5IIc 具有高度的血脑屏障渗透性。

结论：总共合成了 10 种苯并咪唑衍生物并筛选了它们的 AChE 和 BuChE 抑制活性。先导化合物 5Iic 代表了一种有价值的化合物，可作为潜在的 AD 治疗剂进一步开发。