Chemical synthesis, docking studies and biological effects of a pan peroxisome proliferator-activated receptor agonist and cyclooxygenase inhibitor

José Roberto Santin, Flávia D.T. Uchôa, Maria Do Carmo A. Lima, Marcelo M. Rabello, Isabel Daufenback MacHado, Marcelo Z. Hernandes, Angelica A. Amato, Flora Aparecida Milton, Paul Webb, Francisco De Assis Rocha Neves, Suely L. Galdino, Ivan Rocha Pitta, Sandra H.P. Farsky

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

The compound (5Z)-5-[(5-bromo-1H-indol-3-yl)methylene]-3-(4-chlorobenzyl)- thiazolidine-2,4-dione (LYSO-7) was synthesised in order to obtain a new type of anti-inflammatory drug, designed with hybrid features to inhibit cyclooxygenase (COX) and also to activate peroxisome proliferator-activated receptor (PPAR). Results obtained from docking (in silico) studies corroborated with experimental data, showing the potential affinity between the studied ligand and targets. The specificity of LYSO-7 for COX-enzymes was detected by the inhibition of COX-1 and COX-2 activities by 30% and 20%, respectively. In transactivation reporter gene assays LYSO-07 showed a pan partial agonist effect on the three PPAR subtypes (PPARγ, PPARα and PPARβ/δ). The agonist action on PPARγ was also observed by a pharmacological approach, as the reduction in the Escherichia coli lipopolysaccharide (LPS)-induced interleukin 1 beta (IL-1β) secretion and nitric oxide (NO) production by mouse neutrophils was blocked by GW9962, a specific PPARγ antagonist. Additionally, the in vivo effect was measured by reduced carrageenan-induced neutrophil influx into the subcutaneous tissue of mice. Taken together, these data show that LYSO-7 displays a potent in vivo anti-inflammatory effect during the innate acute response, which is dependent on its associated COX inhibitory activities and PPAR activation.

Original languageEnglish (US)
Pages (from-to)689-697
Number of pages9
JournalEuropean Journal of Pharmaceutical Sciences
Volume48
Issue number4-5
DOIs
StatePublished - Mar 12 2013

Keywords

  • Air pouch
  • GW9962
  • Inflammation
  • Interleukin-1β
  • Mice
  • Neutrophils

ASJC Scopus subject areas

  • Pharmaceutical Science

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