New pre-clinical evidence of anti-inflammatory effect and safety of a substituted fluorophenyl imidazole

• Published in: Biomedicine & pharmacotherapy 2019-03, Vol.111, p.1399-1407
• Main Authors: dos Santos Nascimento, Marcus Vinicius Pereira, Mattar Munhoz, Antonio Carlos, De Campos Facchin, Bruno Matheus, Fratoni, Eduarda, Rossa, Thaís Andreia, Mandolesi Sá, Marcus, Campa, Carlo Cosimo, Ciraolo, Elisa, Hirsch, Emilio, Dalmarco, Eduardo Monguilhott
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; ARDS; Bronchoalveolar Lavage Fluid - chemistry; Cytokines - metabolism; Imidazole; Imidazoles - pharmacology; In vivo; Inflammation; Inflammation - drug therapy; Inflammation - metabolism; Inflammation Mediators - pharmacology; Lipopolysaccharides - pharmacology; Lung - drug effects; Lung - metabolism; Male; Mice; NF-κB; Nitric Oxide - metabolism; p38 MAPK; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation - drug effects; Respiratory Distress Syndrome, Adult
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2019.01.052

[Display omitted] •Fluorophenyl imidazole inhibits lung damage in an ARDS induced by LPS model.•Leukocyte migration and exudation were inhibited by fluorophenyl imidazole treatment.•Fluorophenyl imidazole inhibited p38 MAPK and NF-κB phosphorylation in vivo. Acute Respiratory Distress Syndrome (ARDS) is an inflammatory condition with high mortality rates, and there is still no pharmacological approach with proven effectiveness. In the past few years, several imidazole small molecules have been developed to treat conditions in which inflammation plays a central role. In the present work, we hypothesize that a novel substituted fluorophenyl imidazole synthetized by our research group would present in vivo anti-inflammatory effect in an ARDS murine model induced by LPS. Results shows that the fluorophenyl imidazole has the ability to inhibit leukocyte migration to the bronchoalveolar lavage fluid and lung tissue of animals challenged intranasally with LPS. Furthermore, this inhibition is followed with reduction in myeloperoxidase activity, nitric oxide metabolites generation and cytokines (TNF-α, IL-6, IL-17, IFN-γ and IL-10) secretion. This effect is at least partly related to the capacity of the fluorophenyl imidazole in inhibit p38 MAPK and NF-κB phosphorylation. Finally, fluorophenyl imidazole showed no signs of acute oral toxicity in the toxicological protocol suggested by OECD 423. Taken together, the results shows that fluorophenyl imidazole is a promising prototype for the development of a novel anti-inflammatory drug in which p38 MAPK and NF-κB plays a pivotal role.