title: Chemical synthesis, docking studies and biological effects of a pan peroxisome proliferator-activated receptor agonist and cyclooxygenase inhibitor.
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.
authors.affiliation: Departamento de Análises Clínicas e Toxicológicas, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, Brazil.
authors.forename: José Roberto
authors.initials: JR
authors.lastname: Santin
authors.forename: Flávia D T
authors.initials: FD
authors.lastname: Uchôa
authors.forename: Maria do Carmo A
authors.initials: Mdo C
authors.lastname: Lima
authors.forename: Marcelo M
authors.initials: MM
authors.lastname: Rabello
authors.forename: Isabel Daufenback
authors.initials: ID
authors.lastname: Machado
authors.forename: Marcelo Z
authors.initials: MZ
authors.lastname: Hernandes
authors.forename: Angelica A
authors.initials: AA
authors.lastname: Amato
authors.forename: Flora Aparecida
authors.initials: FA
authors.lastname: Milton
authors.forename: Paul
authors.initials: P
authors.lastname: Webb
authors.forename: Francisco de Assis Rocha
authors.initials: Fde A
authors.lastname: Neves
authors.forename: Suely L
authors.initials: SL
authors.lastname: Galdino
authors.forename: Ivan Rocha
authors.initials: IR
authors.lastname: Pitta
authors.forename: Sandra H P
authors.initials: SH
authors.lastname: Farsky
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002351:Carrageenan; D002465:Cell Movement / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008958:Models, Molecular; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists*; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: C583084:5-((5-bromo-1H-indol-3-yl)methylene)-3-(4-chlorobenzyl)thiazolidine-2,4-dione; D000893:Anti-Inflammatory Agents; D016861:Cyclooxygenase Inhibitors; D007211:Indoles; D047492:Peroxisome Proliferator-Activated Receptors; D045162:Thiazolidinediones; D002351:Carrageenan