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

摘要

The transcription factor nuclear factor-kappa B (NF-kappa B) 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-alpha) as inhibitors of NF-kappa B 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). (C) 2016 Elsevier Ltd. All rights reserved.