title: 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.
abstract: 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.
authors: Instituto de Salud Hospital Universitario La Paz - IdiPAZ, Madrid, Spain.
authors: Aranzazu
authors: A
authors: Rodríguez-Sanz
authors: Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcalá, Madrid, Spain.
authors: Patricia
authors: P
authors: Sánchez-Alonso
authors: Instituto de Salud Hospital Universitario La Paz - IdiPAZ, Madrid, Spain. Electronic address: teresa.bellon@salud.madrid.org.
authors: Teresa
authors: T
authors: Bellón
authors: Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcalá, Madrid, Spain. Electronic address: ramon.alajarin@uah.es.
authors: Ramón
authors: R
authors: Alajarín
authors: Instituto de Salud Hospital Universitario La Paz - IdiPAZ, Madrid, Spain.
authors: Virginia
authors: V
authors: Martínez-Cabeza
authors: Hospital Universitario La Paz, Servicio de Nefrología, IdiPAZ, IRSIN, Madrid, Spain.
authors: Rafael
authors: R
authors: Selgas
authors: Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcalá, Madrid, Spain.
authors: Juan J
authors: JJ
authors: Vaquero
authors: Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcalá, Madrid, Spain.
authors: Julio
authors: J
authors: Álvarez-Builla
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005260:Female; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D008070:Lipopolysaccharides / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D061251:Primary Cell Culture; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D000893:Anti-Inflammatory Agents; D001562:Benzimidazoles; D007211:Indoles; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha
keywords: Anti-inflammatory; Cytokine; Pyridazino[1,6-a]benzimidazolium; Pyridazino[1′,6′:1,2]pyrido[3,4-b]indolinium; TNF-α