In pursuit of developing novel cholinesterase (ChE) inhibitors through molecular hybridization theory, a novel series of isoindolin-1,3-dione-based acetohydrazides (compounds 8a–h) was designed, synthesized, and evaluated as possible acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. In vitro results revealed IC50 values ranging from 0.11 ± 0.05 to 0.86 ± 0.02 µM against AChE and 5.7 ± 0.2 to 30.2 ± 2.8 µM against BChE. A kinetic study was conducted on the most potent compound, 8a, to ascertain its mode of inhibition, revealing its competitive mode against AChE. Furthermore, the binding interaction modes of the most active compound within the AChE active site was elucidated. Molecular dynamics simulations of compound 8a were performed to assess the stability of the 8a-AChE complex. In silico pharmacokinetic predictions for the most potent compounds indicated their potential as promising lead structure for the development of new anti-Alzheimer’s disease (anti-AD) agents.

中文翻译：

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新型异吲哚啉-1,3-二酮乙酰肼衍生物的抗胆碱酯酶活性：设计、合成、生物学评价、分子动力学研究

为了通过分子杂交理论开发新型胆碱酯酶（ChE）抑制剂，设计、合成了一系列新型异吲哚啉-1,3-二酮乙酰肼（化合物8a-h），并评估其可能的乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶(BChE) 抑制剂。体外结果显示，针对 AChE 的 IC50 值范围为 0.11 ± 0.05 至 0.86 ± 0.02 µM，针对 BChE 的 IC50 值范围为 5.7 ± 0.2 至 30.2 ± 2.8 µM。对最有效的化合物 8a 进行了动力学研究，以确定其抑制模式，揭示其对抗乙酰胆碱酯酶的竞争模式。此外，还阐明了 AChE 活性位点内最活跃的化合物的结合相互作用模式。对化合物 8a 进行分子动力学模拟以评估 8a-AChE 复合物的稳定性。对最有效的化合物的计算机药代动力学预测表明，它们有潜力作为开发新型抗阿尔茨海默病（抗 AD）药物的先导结构。