Identifying New Isatin Derivatives with GSK-3β Inhibition Capacity through Molecular Docking and Bioassays

The semi-synthesis of 11 isatin derivatives was achieved through bimolecular nucleophilic substitution and click chemistry. Seven new compounds were obtained. All chemical structures were determined by infrared spectroscopy (IR), nuclear magnetic resonance spectrometry (NMR) and high-resolution mass spectrometry (HRMS) data. These derivatives were evaluated for their anti-GSK-3b activity and all isatin derivatives (N-alkyl and 1,2,3-triazolic) exhibited strong inhibitory activity, with 2b and 4h exhibiting remarkable potency. In addition, docking studies were performed with 2b and 2e models to unravel the molecular mechanism underlying the polar interactions on the GSK-3b ATP-binding site.

本研究通过双分子亲核取代反应与点击化学方法，完成了11个靛红衍生物的半合成，共获得7种全新化合物。所有化合物的化学结构均通过红外光谱（infrared spectroscopy, IR）、核磁共振波谱（nuclear magnetic resonance spectrometry, NMR）及高分辨质谱（high-resolution mass spectrometry, HRMS）数据进行了确证。随后对这些衍生物的抗GSK-3b活性开展了评价，结果显示所有靛红衍生物（包括N-烷基取代型与1,2,3-三唑型）均表现出较强的抑制活性，其中化合物2b与4h的抑制活性尤为突出。此外，本研究以化合物2b和2e为模型进行了分子对接研究，以阐明其在GSK-3b ATP结合位点上的极性相互作用分子机制。