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

Davana S Gonçalves; Samara M de S Melo; Andrey P Jacomini; Michael J V da Silva; Karlos E Pianoski; Franciele Q Ames; Rafael P Aguiar; Alisson Felipe Oliveira; Hélito Volpato; Danielle L Bidóia; Celso V Nakamura; Ciomar A Bersani-Amado; Davi F Back; Sidnei Moura; Fávero R Paula; Fernanda A Rosa

doi:10.1016/j.bmc.2020.115549

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. Epub 2020 May 12.

Authors

Davana S Gonçalves¹, Samara M de S Melo¹, Andrey P Jacomini¹, Michael J V da Silva¹, Karlos E Pianoski¹, Franciele Q Ames², Rafael P Aguiar², Alisson Felipe Oliveira³, Hélito Volpato⁴, Danielle L Bidóia⁴, Celso V Nakamura⁴, Ciomar A Bersani-Amado², Davi F Back⁵, Sidnei Moura⁶, Fávero R Paula³, Fernanda A Rosa⁷

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: farosa@uem.br.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Inflammatory Agents / chemical synthesis*
Anti-Inflammatory Agents / metabolism
Anti-Inflammatory Agents / pharmacology
Anti-Inflammatory Agents / therapeutic use
Binding Sites
Catalytic Domain
Cell Line
Cell Survival / drug effects
Cyclooxygenase 2 / chemistry
Cyclooxygenase 2 / metabolism
Cyclooxygenase 2 Inhibitors / chemical synthesis
Cyclooxygenase 2 Inhibitors / metabolism
Cyclooxygenase 2 Inhibitors / pharmacology
Cyclooxygenase 2 Inhibitors / therapeutic use
Edema / chemically induced
Edema / drug therapy
Humans
Mice
Molecular Conformation
Molecular Docking Simulation
Peroxidase / metabolism
Pyridones / chemistry*
Pyridones / metabolism
Pyridones / therapeutic use
Stereoisomerism
Structure-Activity Relationship

Substances

Anti-Inflammatory Agents
Cyclooxygenase 2 Inhibitors
Pyridones
2-hydroxypyridine
Peroxidase
Cyclooxygenase 2