1. Design, Synthesis, and Structure-Activity Relationship Study of Novel Indole-2-carboxamide Derivatives as Anti-inflammatory Agents for the Treatment of Sepsis.
- Author
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Liu Z, Tang L, Zhu H, Xu T, Qiu C, Zheng S, Gu Y, Feng J, Zhang Y, and Liang G
- Subjects
- Animals, Anti-Inflammatory Agents, Non-Steroidal chemical synthesis, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Dose-Response Relationship, Drug, Indoles chemical synthesis, Indoles chemistry, Interleukin-6 antagonists & inhibitors, Interleukin-6 genetics, Lipopolysaccharides antagonists & inhibitors, Lipopolysaccharides pharmacology, Macrophages drug effects, Male, Mice, Mice, Inbred C57BL, Molecular Structure, Piperazines chemical synthesis, Piperazines chemistry, Structure-Activity Relationship, Tumor Necrosis Factor-alpha antagonists & inhibitors, Tumor Necrosis Factor-alpha genetics, Anti-Inflammatory Agents, Non-Steroidal chemistry, Anti-Inflammatory Agents, Non-Steroidal therapeutic use, Drug Design, Indoles pharmacology, Piperazines pharmacology, Sepsis drug therapy
- Abstract
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 were 14f and 14g. They were found to effectively reduce LPS-induced pulmonary inflammation and overexpression of a series of inflammatory mediators. Furthermore, in vivo administration of 14f and 14g resulted 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.
- Published
- 2016
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