Design, synthesis and structure-activity relationship studies of 4-indole-2-arylaminopyrimidine derivatives as anti-inflammatory agents for acute lung injury

Abstract

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS), a clinically high mortality disease, has not been effectively treated till now, and the development of anti-acute lung injury drugs is imminent. Acute lung injury was efficiently treated by inhibiting the cascade of inflammation, and reducing the inflammatory response in the lung. A series of novel compounds with highly efficient inhibiting the expression of inflammatory factors were designed by using 4-indolyl-2-aminopyrimidine as the core skeleton. Totally eleven 4-indolyl-2-arylaminopyrimidine derivatives were designed and synthesized. As well, the related anti -ALI activity of these compounds was evaluated. Compounds 6c and 6h showed a superior activity among these compounds, and the inhibition rate of IL-6 and IL-8 release ranged from 62% to 77%, and from 65% to 72%, respectively. Furthermore, most of compounds had no significant cytotoxicity in vitro . The infiltration of inflammatory cells into lung tissue significantly reduced by using compound 6h (20 mg/kg) in the ALI mice model, which achieved the effect of protecting lung tissue and improving ALI. In addition, the inflammatory response was inhibited by using compound 6h through inhibiting phosphorylation of p-38 and ERK in MAPK signaling pathway, and resulted in protective effect on ALI. These data indicated that compound 6h showed good anti-inflammatory activity in vitro and in vivo , which was expected to become a leading compound for the treatment of ALI.

Remifentanil modulates the TLR4‑mediated MMP‑9/TIMP1 balance and NF‑κB/STAT3 signaling in LPS‑induced A549 cells

“…This is facilitated following the activation of second messengers including cAMP and cGMP and related signaling pathways including NFκB signaling and the PI3K/Akt pathway (6). Although numerous studies have previously revealed that inflammatory factors including TNF-α and IL-6 can become activated during ALI (7)(8)(9), the use of anti-inflammatory drugs (such as sivelestat and simvastatin) in clinical practice was not able to effectively reduce the mortality rate which is estimated as 30-40% globally (10). To date, no effective prevention or treatment measures exist for septic ALI (11).…”

Small Molecules as Anti‐inflammatory Agents: Molecular Mechanisms and Heterocycles as Inhibitors of Signaling Pathways

“…Further, compound 21 b inhibits the phosphorylation of p-38 and ERK in the MAPK signaling pathway (Figure 13). [120] Kalčic et al reported the synthesis and anti-inflammatory activity of 5-butyl-4-(4-benzyloxyphenyl)-6-phenylpyrimidin-2-amine, and their difluorinated analogs. Compounds (22 a, and 22 b) have shown inhibition of PGE2 production nanomolar in comparison with compound 22 c which displayed activity at IC 50 of 4.83 μM.…”

Exploring Potential of Indole Derivatives: A Brief Review

“…Furthermore, to suggest a possible relationship between anticancer effects and to investigate the antioxidant properties, DPPH and ABTS tests were performed, together with fluorescence assays on 3T3-L1 cells. synthesized and 4-indole-2arylaminopyrimidine derivatives as anti-inflammatory agents for acute lung injury [31]. Compounds 6c and six h showed superior activity, and the inhibition rate of IL-6 and IL-8 release ranged from 62% to 77% and from 65% to 72%, respectively.…”