Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382481, Gujarat, India.
Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382481, Gujarat, India.
Bioorg Med Chem Lett. 2019 Apr 1;29(7):917-922. doi: 10.1016/j.bmcl.2019.01.038. Epub 2019 Jan 31.
Following our research for human dihydroorotate dehydrogenase (hDHODH) inhibitors as anticancer agents, herein we describe 3D QSAR-based design, synthesis and in vitro screening of 2-,4,-6-, and/or 7-substituted quinoline derivatives as hDHODH inhibitors and anticancer agents. We have designed 2-,4,-6-, and/or 7-substituted quinoline derivatives and predicted their hDHODH inhibitory activity based on 3D QSAR study on 45 substituted quinoline derivatives as hDHODH inhibitors, and also predicted toxicity. Designed compounds were docked into the binding site of hDHODH. Designed compounds which showed good predictive activity, no toxicity, and good docking score were selected for the synthesis, and in vitro screening as hDHODH inhibitors in an enzyme inhibition assay, and anticancer agents in MTT assay against cancer cell lines (HT-29 and MDA-MB-231). Synthesized compounds 7 and 14 demonstrated IC value of 1.56 µM and 1.22 µM, against hDHODH, respectively, and these are our lead compounds for the development of new hDHODH inhibitors and anticancer agents.
在我们研究人源二氢乳清酸脱氢酶 (hDHODH) 抑制剂作为抗癌剂之后，本文描述了基于 3D-QSAR 的设计、合成和体外筛选 2-、4-、6- 和/或 7-取代喹啉衍生物作为 hDHODH 抑制剂和抗癌剂。我们设计了 2-、4-、6- 和/或 7-取代喹啉衍生物，并基于对 45 种取代喹啉衍生物作为 hDHODH 抑制剂的 3D-QSAR 研究，预测了它们的 hDHODH 抑制活性，同时也预测了毒性。设计的化合物被对接进入 hDHODH 的结合位点。选择具有良好预测活性、无毒性和良好对接评分的设计化合物进行合成，并在酶抑制测定中进行体外筛选，作为 hDHODH 抑制剂，以及在 MTT 测定中针对癌细胞系 (HT-29 和 MDA-MB-231) 的抗癌剂。合成的化合物 7 和 14 对 hDHODH 的 IC 值分别为 1.56 µM 和 1.22 µM，它们是我们开发新型 hDHODH 抑制剂和抗癌剂的先导化合物。
