Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
College of Pharmacy, Yeungnam University, Gyeongsan 38541, Korea.
Molecules. 2020 Sep 25;25(19):4400. doi: 10.3390/molecules25194400.
Isatin derivatives potentially act on various biological targets. In this article, a series of novel isatin-hydrazones were synthesized in excellent yields. Their cytotoxicity was tested against human breast adenocarcinoma (MCF7) and human ovary adenocarcinoma (A2780) cell lines using MTT assay. Compounds (IC = 1.51 ± 0.09 µM) and (IC = 3.56 ± 0.31) showed excellent activity against MCF7, whereas compound showed considerable cytotoxicity against both tested cell lines, MCF7 (IC = 5.46 ± 0.71 µM) and A2780 (IC = 18.96± 2.52 µM), respectively. Structure-activity relationships (SARs) revealed that, halogen substituents at 2,6-position of the C-ring of isatin-hydrazones are the most potent derivatives. In-silico absorption, distribution, metabolism and excretion (ADME) results demonstrated recommended drug likeness properties. Compounds (IC = 0.245 µM) and (IC = 0.300 µM) exhibited good inhibitory activity against the cell cycle regulator CDK2 protein kinase compared to imatinib (IC = 0.131 µM). A molecular docking study of and confirmed both compounds as type II ATP competitive inhibitors that made interactions with ATP binding pocket residues, as well as lacking interactions with active state DFG motif residues.
靛红衍生物可能作用于多种生物靶点。在本文中，我们以优异的产率合成了一系列新型的靛红腙。采用 MTT 法检测它们对人乳腺癌（MCF7）和人卵巢腺癌（A2780）细胞系的细胞毒性。化合物 （IC = 1.51 ± 0.09 μM）和 （IC = 3.56 ± 0.31）对 MCF7 表现出优异的活性，而化合物 对两种测试的细胞系 MCF7（IC = 5.46 ± 0.71 μM）和 A2780（IC = 18.96 ± 2.52 μM）均显示出相当的细胞毒性。构效关系（SAR）表明，C 环上 2,6 位取代的卤素取代基是最有效的衍生物。基于计算机的吸收、分布、代谢和排泄（ADME）结果表明具有推荐的药物相似性特性。化合物 （IC = 0.245 μM）和 （IC = 0.300 μM）对细胞周期调节因子 CDK2 蛋白激酶的抑制活性优于伊马替尼（IC = 0.131 μM）。与 和 的分子对接研究证实，这两种化合物均为 II 型 ATP 竞争性抑制剂，与 ATP 结合口袋残基相互作用，而与活性状态 DFG 基序残基缺乏相互作用。
