Synthesis and biological evaluation of pyridazino[1′,6′:1,2]pyrido[3,4-b]indolinium and pyridazino[1,6-a]benzimidazolium salts as anti-inflammatory agents

• Synthesis of new pyridazino[1′,6′:1,2]pyrido[3,4-b]indolinium salts.
• Synthesis of new pyridazino[1,6-a]benzimidazolium salts.
• Evaluation of cell viability and inhibition of TNF-α production for the series.
• IC50 of 4.49, 3.91 and 1.82 μM in THP-1, PMBCs and monocytes for 1e.
• 1e inhibits IL-12 production in dendritic cells and TNF-production in vivo.

Condensed polycyclic heteroaromatic cations bearing a bridgehead nitrogen with pyridazino[1′,6′:1,2]pyrido[3,4-b]indolinium and pyridazino[1,6-a]benzimidazolium structures were assayed as inhibitors of LPS-induced TNF-α production by THP-1 cells. The hit compound 1e, which had the best IC50 value (4.49 μM) and low toxicity, was further assayed on human PMBCs (IC50 3.91 μM) and monocytes (IC50 1.82 μM). This compound also inhibited TNF-α production following poly I:C stimulation of human monocytes and monocyte-derived dendritic cells; in the latter case, inhibition of IL-12 production was also observed. Compound 1e was also able to inhibit TNF-α expression at the transcriptional level and proved to be effective in vivo. Compound 1e is an interesting potential therapeutic agent in IMIDs.

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