Design of Balanced Cyclooxygenase Inhibitors Based on Natural Anti-inflammatory Ascidian Metabolites and Celecoxib.
ChemMedChem
; 18(23): e202300468, 2023 12 01.
Article
de En
| MEDLINE
| ID: mdl-37815017
ABSTRACT
The serious adverse effects caused by non-selective and selective cyclooxygenase-2 (COX-2) inhibitors remain significant concerns for current anti-inflammatory drugs. In this study, we present the design and synthesis of a novel series of celecoxib analogs incorporating a hydrazone linker, which were subjected to in silico analysis to compare their binding poses with those of clinically used nonsteroidal anti-inflammatory drugs (NSAIDs) against COX-1 and COX-2. The synthesized analogs were evaluated for their inhibitory activity against both COX enzymes, and compound 6 m, exhibiting potent balanced inhibition, was selected for subsequent inâ
vitro anti-inflammatory assays. Treatment with 6 m effectively suppressed the NF-κB signaling pathway in lipopolysaccharide (LPS)-stimulated murine RAW264.7 macrophages, resulting in reduced expression of pro-inflammatory factors such as inducible nitric oxide synthase (iNOS), COX-2, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1ß, as well as decreased production of prostaglandin E2 (PGE2 ), nitric oxide (NO), and reactive oxygen species (ROS). However, 6 m has no effect on the MAPK signaling pathway. Therefore, due to its potent inâ
vitro anti-inflammatory activity coupled with lack of cytotoxicity, 6 m represents a promising candidate for further development as a new lead compound targeting inflammation.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Urochordata
Limites:
Animals
Langue:
En
Journal:
ChemMedChem
Sujet du journal:
FARMACOLOGIA
/
QUIMICA
Année:
2023
Type de document:
Article
Pays d'affiliation:
Chine