Discovery of 1,3-disubstituted prop-2-en-1-one derivatives as inhibitors of neutrophilic inflammation via modulation of MAPK and Akt pathways.
J Enzyme Inhib Med Chem
; 39(1): 2402988, 2024 Dec.
Article
in En
| MEDLINE
| ID: mdl-39297697
ABSTRACT
Targeting neutrophil function has gained attention as a propitious therapeutic strategy for diverse inflammatory diseases. Accordingly, a series of enone-based derivatives were developed to inhibit neutrophil-mediated inflammation, showing promise for treating inflammatory diseases. These compounds fall into two clusters with distinct effects one inhibits neutrophilic superoxide (SO) anion production and elastase release triggered by N-formyl-Met-Leu-Phe (fMLF), with compound 6a being most effective (IC50 values of 1.23 and 1.37 µM, respectively), affecting c-Jun N-terminal kinase (JNK) and Akt phosphorylation. The second cluster suppresses formation of SO anion without affecting elastase levels, surpassed by compound 26a (IC50 of 1.56 µM), which attenuates various mitogen-activated protein kinases (MAPKs) with minimal Akt impact. Notably, none of the tested compounds showed cytotoxicity in human neutrophils, underscoring their potential as therapeutic agents against inflammatory diseases.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Dose-Response Relationship, Drug
/
Proto-Oncogene Proteins c-akt
/
Inflammation
/
Neutrophils
Limits:
Humans
Language:
En
Journal:
J Enzyme Inhib Med Chem
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2024
Document type:
Article
Affiliation country:
Egypt
Country of publication:
United kingdom