title: Synthesis and anti-inflammatory activity evaluation of a novel series of 6-phenoxy-[1,2,4]triazolo[3,4-a]phthalazine-3-carboxamide derivatives.
abstract: 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 50mg/kg intraperitoneal (i.p.), with equal efficacy as the positive control indomethacin (100mg/kg i.p.; 59.21% inhibition).
authors.affiliation: Key Laboratory of Natural Resources and Functional Molecules of the Changbai Mountain, Affiliated Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China.
authors.forename: Da-Chuan
authors.initials: DC
authors.lastname: Liu
authors.affiliation: Medicinal Chemistry and Pharmacology Institute, Inner Mongolia University for the Nationalities, Tongliao, Inner Mongolia 208002, China; Affiliated Hospital of Inner Mongolia University for Nationalities, Tongliao 028000, Inner Mongolia, China.
authors.forename: Guo-Hua
authors.initials: GH
authors.lastname: Gong
authors.affiliation: Medicinal Chemistry and Pharmacology Institute, Inner Mongolia University for the Nationalities, Tongliao, Inner Mongolia 208002, China.
authors.forename: Cheng-Xi
authors.initials: CX
authors.lastname: Wei
authors.affiliation: Key Laboratory of Natural Resources and Functional Molecules of the Changbai Mountain, Affiliated Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China. Electronic address: xjjin@ybu.edu.cn.
authors.forename: Xue-Jun
authors.initials: XJ
authors.lastname: Jin
authors.affiliation: Key Laboratory of Natural Resources and Functional Molecules of the Changbai Mountain, Affiliated Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China. Electronic address: zsquan@ybu.edu.cn.
authors.forename: Zhe-Shan
authors.initials: ZS
authors.lastname: Quan
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D006367:HeLa Cells; D006801:Humans; D007274:Injections, Intraperitoneal; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism; D010793:Phthalazines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014992:Xylenes
chemical_list: C000611972:6-(3-tolyloxy)-(1,2,4)triazolo(3,4-a)phthalazine-3-carboxamide; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016328:NF-kappa B; D010793:Phthalazines; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; D014992:Xylenes
keywords: 3-Carboxamide triazole; Anti-inflammatory; MTT; Nuclear factor-κB; Phthalazine; Synthesis; TNF-α