Synthesis and In vitro and In silico Anti-inflammatory Activity of New Thiazolidinedione-quinoline Derivatives

Author:

da Silva Sandra Elizabeth Barbosa12,da Silva Moura José Arion1,Branco Júnior Jeann Fabiann1,de Moraes Gomes Paulo André Teixeira1,de Paula Simão Kalebe Silva1,Francisco Viana Douglas Carvalho1,de Freitas Ramalho Eduardo Augusto Vasconcelos1,de Melo Gomes João Victor1,Pereira Michelly Cristiny13,da Rocha Pitta Maira Galdino1,da Rocha Pitta Ivan1,da Rocha Pitta Marina Galdino1

Affiliation:

1. Federal University of Pernambuco, Laboratory of Design and Drug Synthesis - LPSF, Recife, PE, Brazil

2. Federal University of Pernambuco, Keizo Asami Institute - iLIKA, Recife, PE, Brazil

3. Federal University of Pernambuco, Laboratory of Immunomodulation and New Therapeutic Approaches - LINAT, Recife, PE, Brazil

Abstract

Background: Inflammation is a series of complex defense-related reactions. The inflammation cascade produces various pro-inflammatory mediators. Unregulated production of these pro-inflammatory mediators can lead to a wide range of diseases, including rheumatoid arthritis, sepsis, and inflammatory bowel disease. In the literature, the anti-inflammatory action of quinoline and thiazolidinedione nuclei are well established, alone, and associated with other nuclei. The synthesis of hybrid molecules is a strategy for obtaining more efficient molecules due to the union of pharmacophoric nuclei known to be related to pharmacological activity. Objective: Based on this, this work presents the synthesis of thiazolidinedione-quinoline molecular hybrids and their involvement in the modulation of cytokines involved in the inflammatory reaction cascade. Methods: After synthesis and characterization, the compounds were submitted to cell viability test (MTT), ELISA IFN-γ and TNF-α, adipogenic differentiation, and molecular docking assay with PPARy and COX-2 targets. Results: LPSF/ZKD2 and LPSF/ZKD7 showed a significant decrease in the concentration of IFN- γ and TNF-α, with a dose-dependent behavior. LPSF/ZKD4 at a concentration of 50 μM significantly reduced IL-6 expression. LPSF/ZKD4 demonstrates lipid accumulation with significant differences between the untreated and negative control groups, indicating a relevant agonist action on the PPARγ receptor. Molecular docking showed that all synthesized compounds have good affinity with PPARγ e COX-2, with binding energy close to -10,000 Kcal/mol. Conclusion: These results demonstrate that the synthesis of quinoline-thiazolidinedione hybrids may be a useful strategy for obtaining promising candidates for new anti-inflammatory agents.

Funder

FINEP

Publisher

Bentham Science Publishers Ltd.

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