Design, Synthesis, and Structure-Activity Relationship Study of Novel Indole-2-carboxamide Derivatives as Anti-inflammatory Agents for the Treatment of Sepsis
Design, Synthesis, and Structure-Activity Relationship Study of Novel Indole-2-carboxamide Derivatives as Anti-inflammatory Agents for the Treatment of Sepsis
复制标题
新型吲哚-2-甲酰胺衍生物作为治疗脓毒症抗炎药的设计、合成及构效关系研究
DOI：
10.1021/acs.jmedchem.5b02006
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发表时间：
2016
影响因子：
7.3
通讯作者：
Liang Guang
中科院分区：
文献类型：
--
作者：
Liu Zhiguo;Tang Longguang;Zhu Heping;Xu Tingting;Qiu Chenyu;Zheng Suqing;Gu Yugui;Feng Jianpeng;Zhang Yali;Liang Guang
脓毒症的特征是全身炎症反应综合征。据报道吲哚衍生物表现出多种生物活性。本研究报告了一系列新的吲哚-2-甲酰胺衍生物的设计和合成，并在 RAW 264.7 巨噬细胞中筛选其抗炎活性。这些衍生物中的大多数可有效抑制脂多糖 (LPS) 诱导的肿瘤坏死因子 α (TNF-α) 和白细胞介素 6 (IL-6) 的表达。还进行了初步的构效关系分析。结果表明，所制备的系列中最有希望的化合物是14f和14g。研究发现它们可以有效减少 LPS 诱导的肺部炎症和一系列炎症介质的过度表达。此外，体内施用14f和14导致小鼠肺组织病理学显着改善，且对器官没有毒性。综上所述，这些数据表明新发现的吲哚-2-甲酰胺衍生物对于炎症性疾病的进一步治疗特别有用。
Sepsis is characterized by a systemic inflammatory response syndrome. Derivatives of indole have been reported to exhibit diverse biological activities. This study reports on the design and synthesis of a new series of indole-2-carboxamide derivatives, which are screened for their anti-inflammatory activities in RAW 264.7 macrophages. A majority of these derivatives effectively inhibited lipopolysaccharides (LPS)-induced expression of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6). Preliminary structure–activity relationship analysis was also conducted. The results indicate that the most promising compounds in the prepared series were14fand14g. They were found to effectively reduce LPS-induced pulmonary inflammation and overexpression of a series of inflammatory mediators. Furthermore, in vivo administration of14fand14gresulted in remarkable lung histopathological improvements in mice without toxicity in organs. Taken together, these data indicate that the newly discovered indole-2-carboxamide derivatives could be particularly useful for further treatment in inflammatory diseases.