Dioxoisoindolines have been included as a pharmacophore group in diverse drug-like molecules with a wide range of biological activity. Various reports have shown that phthalimide derivatives are potent inhibitors of AChE, a key enzyme involved in the deterioration of the cholinergic system during the development of Alzheimer’s disease. In the present study, 2-(2-(3,4-dimethoxyphenyl)ethyl)isoindoline-1,3-dione was synthesized, crystallized and evaluated as an AChE inhibitor. The geometric structure of the crystal and the theoretical compound (from molecular modeling) were analyzed and compared, finding a close correlation. The formation of the C6–H6···O19 interaction could be responsible for the non-negligible out of phenyl plane deviation of the C19 methoxy group, the O3 from the carbonyl group lead to C16–H16···O3i intermolecular interactions to furnish C(9) and C(14) infinite chains within the (− 4 0 9) and (− 3 1 1) families of planes. Finally, the biological experiments reveal that the isoindoline-1,3-dione exerts a good competitive inhibition on AChE (Ki = 0.33–0.93 mM; 95% confidence interval) and has very low acute toxicity (LD50 > 1600 mg/kg) compared to the AChE inhibitors currently approved for clinical use.

中文翻译：

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2-（2-（3,4-二甲氧基苯基）乙基）异吲哚啉-1,3-二酮作为AChE抑制剂的晶体结构，DFT计算和评估

二氧代异吲哚啉已作为药效基团包含在具有广泛生物活性的各种药物样分子中。各种报道表明，邻苯二甲酰亚胺衍生物是AChE的有效抑制剂，AChE是阿尔茨海默氏病发展过程中与胆碱能系统退化有关的关键酶。在本研究中，合成2-（2-（3-（3,4-二甲氧基苯基）乙基）异吲哚啉-1,3-二酮，将其结晶并评估为AChE抑制剂。分析和比较了晶体的几何结构和理论化合物（根据分子模型），发现密切相关。C6-H6···O19相互作用的形成可能是导致C19甲氧基的苯基平面偏差不可忽略的原因，来自羰基的O3导致C16–H16···O3i分子间相互作用，从而在（− 4 0 9）和（− 3 1 1）平面族内提供C（9）和C（14）无限链。最后，生物学实验表明，异吲哚啉-1,3-二酮对AChE具有良好的竞争抑制作用（Ki = 0.33–0.93 mM； 95％置信区间），并且急性毒性极低（LD50> 1600 mg / kg）。目前批准用于临床的AChE抑制剂。