In this article, we aimed to (1) synthesize novel 3-substitue 2-methyl indole analogs, and (2) evaluate their biological activities against Acetylcholinesterase enzyme (AChE) and Glutathione S-transferase enzyme (GST), (3) predict ADMET and pharmacokinetic properties of the 3-substitue 2-methyl indole analogs (4) reveal the possible interactions between 3-substitue 2-methyl indole analogs and selected enzymes. In vitro enzyme inhibition studies revealed the 3-substitue 2-methyl indole analogs exhibited moderate to good inhibitory activities against AChE and GST enzymes. 2-azido-1-(2-methyl-1H-indol-3-yl)ethanone synthesized was a good inhibitor with the lowest Ki value for both enzymes. Furthermore, a molecular docking study of 3-substitue 2-methyl indole analogs was carried out in the active site of AChE/GST to gain insight into the interaction modes of the synthesized analogs and rationalized structure-activity relationship. The binding energies of the AChE-3-substitue 2-methyl indole analogs’ complexes were found between −9.3 and −6.0 kcal/mol, and the binding energies of the GST-3-substitue 2-methyl indole analogs’ complexes were also found between −11.1 and −7.5 kcal/mol.

在本文中，我们旨在 (1) 合成新型 3-取代基 2-甲基吲哚类似物，(2) 评估它们对乙酰胆碱酯酶 (AChE) 和谷胱甘肽 S-转移酶 (GST) 的生物活性，(3) 预测 ADMET 3-取代 2-甲基吲哚类似物 (4) 的药代动力学特性揭示了 3-取代 2-甲基吲哚类似物与选定酶之间可能的相互作用。体外酶抑制研究表明，3-取代基 2-甲基吲哚类似物对 AChE 和 GST 酶表现出中等至良好的抑制活性。合成的 2-azido-1-(2-methyl-1H-indol-3-yl)ethanone 是一种良好的抑制剂，两种酶的 Ki 值最低。此外，在 AChE/GST 的活性位点进行了 3-取代 2-甲基吲哚类似物的分子对接研究，以深入了解合成类似物的相互作用模式和合理的构效关系。AChE-3-取代基 2-甲基吲哚类似物复合物的结合能介于 -9.3 和 -6.0 kcal/mol 之间，GST-3-取代基 2-甲基吲哚类似物复合物的结合能也被发现介于 -11.1 和 -7.5 kcal/mol 之间。