Discovery of Novel Orally Active Tetrahydro-Naphthyl-N-Acylhydrazones with In Vivo Anti-TNF-α Effect and Remarkable Anti-Inflammatory Properties

• Published in: PloS one Vol. 11; no. 5; p. e0156271
• Main Authors: Cordeiro, Natália M, Freitas, Rosana H C N, Fraga, Carlos A M, Fernandes, Patricia D
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 26.05.2016; Public Library of Science (PLoS)
• Subjects: Administration, Oral; Animals; Anti-inflammatory agents; Anti-Inflammatory Agents - administration & dosage; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Biocompatibility; Biology and Life Sciences; Biosynthesis; Boronic Acids - administration & dosage; Boronic Acids - chemistry; Boronic Acids - pharmacology; Carrageenan; Carrageenan - toxicity; Cell lineage; Chemistry; Cytokines; Cytotoxicity; Drug Discovery; Enzyme inhibitors; Gene expression; Hydrazones - administration & dosage; Hydrazones - chemistry; Hydrazones - pharmacology; I-kappa B Kinase - antagonists & inhibitors; Inflammation; Inflammation - chemically induced; Inflammation - drug therapy; Inflammation - metabolism; Inhibitors; Kinases; Laboratories; Leukocyte migration; Leukocytes; Medicine and Health Sciences; Mice; Myelosuppression; NF-kappa B - metabolism; NF-κB protein; Nitric oxide; Nitric Oxide - metabolism; Oxygen; Pharmaceutical sciences; Pharmacology; Physical properties; Physical Sciences; Proteins; Reactive oxygen species; Reactive Oxygen Species - metabolism; Research and Analysis Methods; Rodents; Signal Transduction - drug effects; Toxicity; Transcription factors; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Brazil; Rio de Janeiro Brazil
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0156271

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.