Synthesis of novel 3,5,6-trisubstituted 2-pyridone derivatives and evaluation for their anti-inflammatory activity

  • Bioorg Med Chem. 2020 Jun 15;28(12):115549. doi: 10.1016/j.bmc.2020.115549.
Davana S Gonçalves  1 ,  Samara M de S Melo  1 ,  Andrey P Jacomini  1 ,  Michael J V da Silva  1 ,  Karlos E Pianoski  1 ,  Franciele Q Ames  2 ,  Rafael P Aguiar  2 ,  Alisson Felipe Oliveira  3 ,  Hélito Volpato  4 ,  Danielle L Bidóia  4 ,  Celso V Nakamura  4 ,  Ciomar A Bersani-Amado  2 ,  Davi F Back  5 ,  Sidnei Moura  6 ,  Fávero R Paula  3 ,  Fernanda A Rosa  7
Affiliations
  • 1. Departamento de Química, Universidade Estadual de Maringá (UEM), 87030-900 Maringá, PR, Brazil.
  • 2. Departamento de Farmacologia e Terapêutica, Universidade Estadual de Maringá (UEM), 87030-900 Maringá, PR, Brazil.
  • 3. Departamento de Farmácia, Universidade Federal do Pampa (UNIPAMPA), 97500-970 Uruguaiana, RS, Brazil.
  • 4. Pós-Graduação em Ciências Biológicas, Universidade Estadual de Maringá (UEM), 87020-900 Maringá, PR, Brazil.
  • 5. Departamento de Química, Universidade Federal de Santa Maria (UFSM), 97110-970 Santa Maria, RS, Brazil.
  • 6. Instituto de Biotecnologia, Universidade de Caxias do Sul (UCS), 295070-560 Caxias do Sul, RS, Brazil.
  • 7. Departamento de Química, Universidade Estadual de Maringá (UEM), 87030-900 Maringá, PR, Brazil. Electronic address: [email protected].
PMID: 32503692 DOI: 10.1016/j.bmc.2020.115549
Abstract

The inflammatory response is the reaction of living tissue to an injury of a foreign nature, such as Infection and irritants, and occurs as part of the body's natural defence response. Compounds capable of inhibiting cyclooxygenase (COX) Enzymes, especially COX-2, have great potential as anti-inflammatory agents. Herein we present the regioselective synthesis of 49 novel compounds based on the 2-pyridone nucleus. The topical anti-inflammatory activity of seventeen compounds was evaluated in mice by croton oil (CO) induced ear edema assay. Most of the compounds exhibited a high level of in vivo anti-inflammatory activity, reducing ear edema and myeloperoxidase (MPO) activity. The most active compounds (2a and 7a) were inhibitors of COX Enzymes. Compound 2a selectively inhibited the COX-2, while 7a was nonselective. Further, the compound 2a showed effective binding at the active site of COX-2 co-crystal by docking molecular study.

Keywords
2-pyridone; Anti-inflammatory; COXs.
Products