title: Discovery of Novel Orally Active Tetrahydro-Naphthyl-N-Acylhydrazones with In Vivo Anti-TNF-α Effect and Remarkable Anti-Inflammatory Properties.
abstract: LASSBio-1524 was designed as inhibitor of the IKK-β (kappa β kinase inhibitor) enzyme, which participates in the activation of the nuclear factor κB (NF-κB) canonical pathway, and its three N-acylhydrazone new analogues, LASSBio-1760, LASSBio-1763 and LASSBio-1764 are now being tested on their anti-inflammatory potential. The activity of these compounds was evaluated with the subcutaneous air pouch induced by carrageenan and by subsequent measurement of tumor necrosis factor-α (TNF-α), nitric oxide (NO) and reactive oxygen species (ROS). In the acute inflammation model, the oral pretreatment with doses from 0.3 to 30 mg/kg of N-acylhydrazone derivatives was able to significantly reduce leukocyte migration to the cavity. Pretreatment with LASSBio-1524 and its analogues also decreased NO, TNF-α and ROS biosynthesis an events closely involved with NF-kB pathway. The tetrahydronaphthyl-N-acylhydrazone derivative LASSBio-1764 was the most promising compound from this series, surpassing even LASSBio-1524. Additionally, none of the compounds demonstrated myelotoxicity or cytotoxicity. Cell viability was assayed and these compounds demonstrated to be safe at different concentrations. Western blot analysis demonstrated that LASSBio-1524 and LASSBio-1760 inhibited NF-κB expression in RAW 264.7 cell lineage. Our data indicate that the tested compounds have anti-inflammatory activity, which may be related to inhibition of leukocyte migration, reducing the production of NO, TNF-α and ROS. LASSBio-1524 and LASSBio-1760, in addition to these features, also reduced p65 nuclear expression assessed by western blot in RAW 264.7 murine cells.
authors.affiliation: Federal University of Rio de Janeiro, Institute of Biomedical Science, Laboratory of Pharmacology of Pain and Inflammation, Rio de Janeiro, Brazil.|Federal University of Rio de Janeiro, Institute of Biomedical Science, Graduate Programm in Pharmacology and Medicinal Chemistry, Rio de Janeiro, Brazil.
authors.forename: Natália M
authors.initials: NM
authors.lastname: Cordeiro
authors.affiliation: Federal University of Rio de Janeiro, Institute of Biomedical Science, Laboratory of Evaluation and Synthesis of Bioactive Substances (LASSBio), Rio de Janeiro, Brazil.|Federal University of Rio de Janeiro, Chemistry Institute, Graduate Programm in Chemistry, Rio de Janeiro, Brazil.
authors.forename: Rosana H C N
authors.initials: RH
authors.lastname: Freitas
authors.affiliation: Federal University of Rio de Janeiro, Institute of Biomedical Science, Graduate Programm in Pharmacology and Medicinal Chemistry, Rio de Janeiro, Brazil.|Federal University of Rio de Janeiro, Institute of Biomedical Science, Laboratory of Evaluation and Synthesis of Bioactive Substances (LASSBio), Rio de Janeiro, Brazil.|Federal University of Rio de Janeiro, Chemistry Institute, Graduate Programm in Chemistry, Rio de Janeiro, Brazil.
authors.forename: Carlos A M
authors.initials: CA
authors.lastname: Fraga
authors.affiliation: Federal University of Rio de Janeiro, Institute of Biomedical Science, Laboratory of Pharmacology of Pain and Inflammation, Rio de Janeiro, Brazil.|Federal University of Rio de Janeiro, Institute of Biomedical Science, Graduate Programm in Pharmacology and Medicinal Chemistry, Rio de Janeiro, Brazil.
authors.forename: Patricia D
authors.identifier: http://orcid.org/0000-0001-6870-6745
authors.initials: PD
authors.lastname: Fernandes
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001897:Boronic Acids / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002351:Carrageenan / Q000633:toxicity; D055808:Drug Discovery; D006835:Hydrazones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D000893:Anti-Inflammatory Agents; D001897:Boronic Acids; D006835:Hydrazones; C000621583:LASSBio-1760; C000621584:LASSBio-1763; C000621585:LASSBio-1764; C558589:N-(4-nitrobenzylidene)-2-naphthohydrazide; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D002351:Carrageenan; D051550:I-kappa B Kinase