School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230031, China.
School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230031, China; Department of Medicinal Chemistry, Anhui Academy of Chinese Medicine, Hefei, 230031, China.
Eur J Med Chem. 2019 Oct 15;180:41-50. doi: 10.1016/j.ejmech.2019.07.004. Epub 2019 Jul 4.
In this work, a series of novel indole-2-amide compounds were designed, synthesized, characterized and the anti-inflammatory activity in vivo were evaluated. Compounds 8a, 10b, 12h, and 12l exhibited marked anti-inflammatory activity in 2,4-Dinitrofluorobenzenethe (DNFB) - induced mice auricle edema model. Further, compounds 8a, 10b and 12h exhibited potential in vitro COX-2 inhibitory activity (IC = 21.86, 23.3 and 23.21 nM, respectively), while the reference drug celecoxib was 11.20 nM. The most promising compound 10b was exhibited the highest selectivity for COX-2 (selectivity index (COX-1/COX-2) = 17.45) and moderate 5-LOX inhibitory activity (IC = 66 nM), which comparable to positive controlled zileuton (IC = 38.91 nM). In addition, the test results showed compounds 10b and 12h no significant cytotoxic activity on normal cells (RAW264.7). Further, at the active sites of the COX-1, COX-2 co-crystals, 3b and 4l showed higher binding forces in the molecular docking study, which consistent with the results of in vitro experiments. These results demonstrated that these compounds had dual inhibitory activity of COX/5-LOX, providing clues for further searching for safer and more effective anti-inflammatory drugs.
在这项工作中，设计、合成、表征了一系列新型吲哚-2-酰胺化合物，并评价了它们的体内抗炎活性。化合物 8a、10b、12h 和 12l 在 2,4-二硝基氟苯（DNFB）诱导的小鼠耳廓水肿模型中表现出显著的抗炎活性。此外，化合物 8a、10b 和 12h 表现出潜在的体外 COX-2 抑制活性（IC = 21.86、23.3 和 23.21 nM，分别），而参考药物塞来昔布为 11.20 nM。最有前途的化合物 10b 对 COX-2 的选择性最高（COX-1/COX-2 选择性指数为 17.45），对 5-LOX 具有中等抑制活性（IC = 66 nM），与阳性对照齐留通（IC = 38.91 nM）相当。此外，试验结果表明化合物 10b 和 12h 在正常细胞（RAW264.7）中没有明显的细胞毒性。进一步的，在 COX-1、COX-2 共晶的活性部位，化合物 3b 和 4l 在分子对接研究中表现出更高的结合力，这与体外实验的结果一致。这些结果表明，这些化合物具有 COX/5-LOX 的双重抑制活性，为进一步寻找更安全、更有效的抗炎药物提供了线索。
