Design, Synthesis, and Structure–Activity Relationship Study of Novel Indole-2-carboxamide Derivatives as Anti-inflammatory Agents for the Treatment of Sepsis

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.