title: Discovery of Novel 2-(piperidin-4-yl)-1H-benzo[d]imidazole Derivatives as Potential Anti-Inflammatory Agents.
abstract: A novel 2-(piperidin-4-yl)-1H-benzo[d]imidazole derivative 5 with good anti-inflammatory activity was identified from our in-house library. Based on hit compound 5, two series of 2-(piperidin-4-yl)-1H-benzo[d]imidazole derivative 6a-g and 7a-h were designed and synthesized as novel anti-inflammatory agents. Most of synthesized compounds exhibited good inhibitory activity on NO and TNF-α production in LPS-stimulated RAW 264.7 macrophages, in which the compound 6e showed most potent inhibitory activity on NO (IC50  = 0.86 μm) and TNF-α (IC50  = 1.87 μm) production. Further evaluation revealed that compound 6e displayed more potent in vivo anti-inflammatory activity than ibuprofen did on xylene-induced ear oedema in mice. Additionally, Western blot analysis revealed that compound 6e could restore phosphorylation level of IκBα and protein expression of p65 NF-κB in LPS-stimulated RAW 264.7 macrophages.
authors.affiliation: Center of Drug Discovery, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Center of Drug Discovery, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Xinning
authors.initials: X
authors.lastname: Wang
authors.affiliation: Center of Drug Discovery, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zong
authors.affiliation: Center of Drug Discovery, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Leilei
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Center of Drug Discovery, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Junhao
authors.initials: J
authors.lastname: Xing
authors.affiliation: Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing, 210009, China.
authors.forename: Jinpei
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Center of Drug Discovery, China Pharmaceutical University, Nanjing, 210009, China.|State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Huibin
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D055808:Drug Discovery; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014992:Xylenes / Q000633:toxicity
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007093:Imidazoles; D008070:Lipopolysaccharides; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D014992:Xylenes
keywords: 2-(piperidin-4-yl)-1H-benzo[d]imidazole derivatives; anti-inflammatory activity; benzimidazole; inflammation