Synthesis and anti-inflammatory activity of new arylidene-thiazolidine-2,4-diones as PPARgamma ligands.
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.
Barros
Cleiton Diniz
CD
Grupo de Pesquisa em Inovação Terapêutica-GPIT, Universidade Federal de Pernambuco, Pernambuco, Brazil.
Amato
Angélica Amorim
AA
de Oliveira
Tiago Bento
TB
Iannini
Karime Bicas Rocha
KB
Silva
Anekécia Lauro da
AL
Silva
Teresinha Gonçalves da
TG
Leite
Elisa Soares
ES
Hernandes
Marcelo Zaldini
MZ
Alves de Lima
Maria do Carmo
Mdo C
Galdino
Suely Lins
SL
Neves
Francisco de Assis Rocha
Fde A
Pitta
Ivan da Rocha
Ida R
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
D000893:Anti-Inflammatory Agents; C000612421:GQ-177; D008024:Ligands; D047495:PPAR gamma; D013450:Sulfones; D045162:Thiazolidinediones; C500090:thiazolidine-2,4-dione; D000077154:Rosiglitazone