title: Synthesis and anti-inflammatory activity of new arylidene-thiazolidine-2,4-diones as PPARgamma ligands.
abstract: Eight new 5-arylidene-3-benzyl-thiazolidine-2,4-diones with halide groups on their benzyl rings were synthesized and assayed in vivo to investigate their anti-inflammatory activities. These compounds showed considerable biological efficacy when compared to rosiglitazone, a potent and well-known agonist of PPARgamma, which was used as a reference drug. This suggests that the substituted 5-arylidene and 3-benzylidene groups play important roles in the anti-inflammatory properties of this class of compounds. Docking studies with these compounds indicated that they exhibit specific interactions with key residues located in the site of the PPARgamma structure, which corroborates the hypothesis that these molecules are potential ligands of PPARgamma. In addition, competition binding assays showed that four of these compounds bound directly to the ligand-binding domain of PPARgamma, with reduced affinity when compared to rosiglitazone. An important trend was observed between the docking scores and the anti-inflammatory activities of this set of molecules. The analysis of the docking results, which takes into account the hydrophilic and hydrophobic interactions between the ligands and the target, explained why the 3-(2-bromo-benzyl)-5-(4-methanesulfonyl-benzylidene)-thiazolidine-2,4-dione compound had the best activity and the best docking score. Almost all of the stronger hydrophilic interactions occurred between the substituted 5-arylidene group of this compound and the residues of the binding site.
authors.affiliation: Grupo de Pesquisa em Inovação Terapêutica-GPIT, Universidade Federal de Pernambuco, Pernambuco, Brazil.
authors.forename: Cleiton Diniz
authors.initials: CD
authors.lastname: Barros
authors.forename: Angélica Amorim
authors.initials: AA
authors.lastname: Amato
authors.forename: Tiago Bento
authors.initials: TB
authors.lastname: de Oliveira
authors.forename: Karime Bicas Rocha
authors.initials: KB
authors.lastname: Iannini
authors.forename: Anekécia Lauro da
authors.initials: AL
authors.lastname: Silva
authors.forename: Teresinha Gonçalves da
authors.initials: TG
authors.lastname: Silva
authors.forename: Elisa Soares
authors.initials: ES
authors.lastname: Leite
authors.forename: Marcelo Zaldini
authors.initials: MZ
authors.lastname: Hernandes
authors.forename: Maria do Carmo
authors.initials: Mdo C
authors.lastname: Alves de Lima
authors.forename: Suely Lins
authors.initials: SL
authors.lastname: Galdino
authors.forename: Francisco de Assis Rocha
authors.initials: Fde A
authors.lastname: Neves
authors.forename: Ivan da Rocha
authors.initials: Ida R
authors.lastname: Pitta
mesh_terms: D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000592:standards; D001667:Binding, Competitive; D003198:Computer Simulation; D006801:Humans; D008024:Ligands; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D011485:Protein Binding; D000077154:Rosiglitazone; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000494:pharmacology; D045162:Thiazolidinediones / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; C000612421:GQ-177; D008024:Ligands; D047495:PPAR gamma; D013450:Sulfones; D045162:Thiazolidinediones; C500090:thiazolidine-2,4-dione; D000077154:Rosiglitazone