Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14176, Iran; Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
Bioorg Med Chem. 2013 Nov 1;21(21):6708-17. doi: 10.1016/j.bmc.2013.08.009. Epub 2013 Aug 13.
A series of 16 novel 1,2,4-triazine derivatives bearing hydrazone moiety (7a-7p) have been designed, synthesized and evaluated for their activity to inhibit IL-1β and TNF-α production. All compounds are reported for the first time. The chemical structures of all compounds were confirmed by spectroscopic methods and elemental analyzes. Most of the synthesized compounds were proved to have potent anti-cytokine activity and low toxicity on PBMC and MCF-7 cell lines. Compounds 7f, 7k, 7l and 7j presented simultaneously good levels of inhibition of both cytokines. Moreover, compound 7l exhibited good anti-inflammatory effect in carrageenan-induced rat paw edema. The results of Western blotting demonstrated that the anti-cytokine potential of compound 7l is mainly mediated through the inhibition of p38 MAPK signaling pathway. Molecular docking was performed to position compound 7l into p38α binding site in order to explore the potential target. The information of this work might be helpful for the design and synthesis of novel scaffold toward the development of new therapeutic agent to fight against inflammatory diseases.
已经设计、合成并评价了一系列带有腙部分的 16 种新型 1,2,4-三嗪衍生物（7a-7p），以评估它们抑制 IL-1β 和 TNF-α 产生的活性。所有化合物均为首次报道。所有化合物的化学结构均通过光谱方法和元素分析得到证实。大多数合成的化合物被证明对 PBMC 和 MCF-7 细胞系具有很强的细胞因子抑制活性和低毒性。化合物 7f、7k、7l 和 7j 同时对两种细胞因子具有良好的抑制作用。此外，化合物 7l 在角叉菜胶诱导的大鼠足肿胀中表现出良好的抗炎作用。Western blot 结果表明，化合物 7l 的细胞因子抑制作用主要通过抑制 p38 MAPK 信号通路来介导。进行了分子对接，将化合物 7l 定位到 p38α 结合位点，以探索潜在的靶标。这项工作的信息可能有助于设计和合成新型支架，以开发治疗炎症性疾病的新型治疗剂。
