Synthesis, molecular modeling and anti-inflammatory activity of new benzo[a]pyrano[2,3-c]phenazine compounds

Abstract

A convenient microwave-assisted three-component synthetic approach was developed for the synthesis of new benzo[a]pyrano[2,3-c]phenazine derivatives starting from benzo[a]phenazin-5-ol, benzaldehyde derivatives, and enaminone derivatives. Sixteen new derivatives were successfully synthesized and identified by spectroscopic data analysis.To analyse the potent anti-inflammatory activity of these new derivatives, the Griess assay and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay were used to assess their effects on NO production in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells and their cytotoxicity on the cell line, respectively. The in vitro tests showed that all products displayed the highly potential NO production inhibition activity with the IC₅₀ values in the range of 0.98-25.43 µM.Besides that, treatment of LPS-stimulated cells with the most potential compounds partially reduced proinflammatory cytokine IL-1β, IL-6 levels in a dose-dependent manner. Molecular docking studies further supported their interaction with inflammation-related targets, suggesting that the benzo[a]pyrano[2,3-c]phenazine scaffold represents a promising basis for further development of anti-inflammatory agents.