title: Synthesis and biological evaluation of 4-alkoxy-6,9-dichloro[1,2,4]triazolo[4,3-a]quinoxalines as inhibitors of TNF-α and IL-6.
abstract: An efficient synthetic method for previously unattainable 4-alkoxy-6,9-dichloro[1,2,4]triazolo[4,3-a]quinoxalines has been established. Reactions between 5,8-dichloro-2,3-dicyanoquinoxaline and alcohols in the presence of triethylamine led to 3-alkoxy-5,8-dichloro-2-cyanoquinoxalines in high to quantitative yields. These compounds were treated with hydrazine giving 3-alkoxy-5,8-dichloro-2-hydrazinoquinoxalines in near quantitative yields, that reacted with triethyl orthoformate to provide the title compounds in high yields. The molecular structure of a member of this family of compounds: 6,9-dichloro-4-ethoxy[1,2,4]triazolo[4,3-a]quinoxaline, was determined by X-ray crystallography. The series of compounds synthesized were evaluated for their potential anti-inflammatory activity as inhibitors of the pro-inflammatory cytokines TNF-α and IL-6. Compounds 8e, 8a, 8b and 8g presented simultaneously good levels of inhibition of both cytokines being compound 8e the most concomitantly potent one. Compounds 8d, 8f and 8h specifically inhibited IL-6 with no significant inhibition of TNF-α. Compound 8c was not significantly active upon TNF-α, and showed no activity upon IL-6.
authors.affiliation: Departamento de Química Orgánica, Facultad de Química, Universidad de Murcia, Campus de Espinardo, 30100 Murcia, Apartado 4021, Spain. anguir@um.es
authors.forename: Antonio
authors.initials: A
authors.lastname: Guirado
authors.forename: José I
authors.initials: JI
authors.lastname: López Sánchez
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Ruiz-Alcaraz
authors.forename: Delia
authors.initials: D
authors.lastname: Bautista
authors.forename: Jesús
authors.initials: J
authors.lastname: Gálvez
mesh_terms: D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D018922:HL-60 Cells; D006801:Humans; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D000093242:Interleukin-6 Inhibitors
chemical_list: D000893:Anti-Inflammatory Agents; D011810:Quinoxalines; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors