Synthesis and anti-inflammatory activity evaluation of a novel series of 6-phenoxy-[1,2,4]triazolo[3,4-a]phthalazine-3-carboxamide derivatives

The transcription factor nuclear factor-κB (NF-κB) controls many physiological processes including inflammation, immunity, and apoptosis. In this study, a novel series of 6-phenoxy-[1,2,4]triazolo[3,4-a]phthalazine-3-carboxamide derivatives were synthesized as potent anti-inflammatory agents, which acted on tumor necrosis factor (TNF-α) as inhibitors of NF-κB activation. We showed that compounds 6h (6-(2,4-dichlorophenoxy)-[1,2,4]triazolo[3,4-a]phthalazine-3-carboxamide) and 6i (6-(3-tolyloxy)-[1,2,4]triazolo[3,4-a]phthalazine-3-carboxamide) showed more prominent anti-inflammatory activity than other compounds, with similar activities as the reference drug dihydrotanshinone; compound 6i showed the lowest cellular toxicity among the tested compounds. In vivo evaluation of the anti-inflammatory activity showed that compound 6i exhibited excellent anti-inflammatory activity with 58.19% inhibition at 50 mg/kg intraperitoneal (i.p.), with equal efficacy as the positive control indomethacin (100 mg/kg i.p.; 59.21% inhibition).

A new series of anti-inflammatory 6-phenoxy-[1,2,4]triazolo[3,4-a]phthalazine-3-carboxamide derivatives were synthesized and their anti-inflammatory activities were evaluated by the luciferase reporter assay. 6-(3-Tolyloxy)-[1,2,4]triazolo[3,4-a]phthalazine-3-carboxamide (compound 6i) had comparable activity with the reference drug dihydrotanshinone with low cellular toxicity. Then, compound 6i was selected for anti-inflammatory evaluation in vivo. The activity screening indicated that compound 6i at 50 mg/kg showed 58.19% inhibition at 0.5 h after i.p. and 38.8% inhibition by p.o.Figure optionsDownload as PowerPoint slide