title: Design, Synthesis, and Structure-Activity Relationship Study of Novel Indole-2-carboxamide Derivatives as Anti-inflammatory Agents for the Treatment of Sepsis.
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.
authors.affiliation: Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University , 1210 University Town, Wenzhou, Zhejiang 325035, China.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University , 1210 University Town, Wenzhou, Zhejiang 325035, China.|Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University , Xiamen 361102, China.
authors.forename: Longguang
authors.initials: L
authors.lastname: Tang
authors.affiliation: Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University , 1210 University Town, Wenzhou, Zhejiang 325035, China.
authors.forename: Heping
authors.initials: H
authors.lastname: Zhu
authors.affiliation: The Second Affiliated Hospital, Wenzhou Medical University , Wenzhou, Zhejiang 325035, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Xu
authors.affiliation: Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University , 1210 University Town, Wenzhou, Zhejiang 325035, China.
authors.forename: Chenyu
authors.initials: C
authors.lastname: Qiu
authors.affiliation: Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University , 1210 University Town, Wenzhou, Zhejiang 325035, China.
authors.forename: Suqing
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Chemical Biology Section in WMU-WU Joint Research Centre, Wenzhou University , Wenzhou, Zhejiang 325035, China.
authors.forename: Yugui
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University , 1210 University Town, Wenzhou, Zhejiang 325035, China.
authors.forename: Jianpeng
authors.initials: J
authors.lastname: Feng
authors.affiliation: Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University , 1210 University Town, Wenzhou, Zhejiang 325035, China.
authors.forename: Yali
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University , 1210 University Town, Wenzhou, Zhejiang 325035, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Liang
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015850:Interleukin-6 / Q000235:genetics; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018805:Sepsis / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics; D000093242:Interleukin-6 Inhibitors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007211:Indoles; D015850:Interleukin-6; D008070:Lipopolysaccharides; D010879:Piperazines; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C000619426:5-(3,3-dimethylureido)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide; C000619425:5-(furan-2-carboxamido)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-2-carboxamide