癌细胞中的多药耐药（MDR）机制很大程度上受谷胱甘肽转移酶 P1-1 (hGSTP1-1) 的影响。使用合成或天然化合物作为 hGSTP1-1 抑制剂被认为是克服 MDR 的有效方法。合成了九种由香豆素-6-磺酰胺与查耳酮衍生物连接组成的化合物，并评估了它们抑制 hGSTP1-1 的能力。在合成衍生物中，化合物5g、5f和5a显示出最有效的抑制作用，IC50值分别为12.2±0.5μM、12.7±0.7和16.3±0.6。最有效的分子 5g 的动力学抑制分析表明，它是目标酶的混合型抑制剂。 5a、5f 和 5g 对人前列腺癌细胞系 DU-145 和 PC3 以及乳腺癌细胞系 MCF-7 的体外细胞毒性评估表明，化合物 5g 对所有测试的细胞表现出最显着的细胞毒性作用细胞系。进行分子对接研究以预测 5g、5f 和 5a 与 hGSTP1-1 结合的结构和分子决定因素。与实验数据一致，结果表明，由于形状互补性（受范德华力、氢键和 π-π 堆积相互作用控制），5g 在三种研究的抑制剂中表现出最低的对接分数。这些研究结果表明，香豆素-查耳酮杂化物为开发安全高效的基于天然产物的敏化剂提供了新的视角，这些敏化剂可以靶向 hGSTP1-1 以达到抗癌目的。版权所有：© 2024 Sabt 等人。这是一篇根据知识共享署名许可条款分发的开放获取文章，允许在任何媒体上不受限制地使用、分发和复制，前提是注明原始作者和来源。

Multidrug resistance (MDR) mechanisms in cancer cells are greatly influenced by glutathione transferase P1-1 (hGSTP1-1). The use of synthetic or natural compounds as hGSTP1-1 inhibitors is considered an effective approach to overcome MDR. Nine compounds consisting of coumarin-6-sulfonamide linked to chalcone derivatives were synthesized and evaluated for their ability to inhibit hGSTP1-1. Among the synthetic derivatives, compounds 5g, 5f, and 5a displayed the most potent inhibitory effect, with IC50 values of 12.2 ± 0.5 μΜ, 12.7 ± 0.7 and 16.3 ± 0.6, respectively. Kinetic inhibition analysis of the most potent molecule, 5g, showed that it behaves as a mixed-type inhibitor of the target enzyme. An in vitro cytotoxicity assessment of 5a, 5f, and 5g against the human prostate cancer cell lines DU-145 and PC3, as well as the breast cancer cell line MCF-7, demonstrated that compound 5g exhibited the most pronounced cytotoxic effect on all tested cell lines. Molecular docking studies were performed to predict the structural and molecular determinants of 5g, 5f, and 5a binding to hGSTP1-1. In agreement with the experimental data, the results revealed that 5g exhibited the lowest docking score among the three studied inhibitors as a consequence of shape complementarity, governed by van der Waals, hydrogen bonds and a π-π stacking interaction. These findings suggest that coumarin-chalcone hybrids offer new perspectives for the development of safe and efficient natural product-based sensitizers that can target hGSTP1-1 for anticancer purposes.Copyright: © 2024 Sabt et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.