Discovery of 1,3-disubstituted prop-2-en-1-one derivatives as inhibitors of neutrophilic inflammation via modulation of MAPK and Akt pathways
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 <b>6a</b> being most effective (IC<sub>50</sub> 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 <b>26a</b> (IC<sub>50</sub> 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.
Authors
- Mohamed El‐Shazly (ORCID: https://orcid.org/0000-0003-0050-8288)
- Tsong‐Long Hwang (ORCID: https://orcid.org/0000-0002-5780-3977)
- Mohammad Abdel‐Halim (ORCID: https://orcid.org/0000-0003-1326-4219)
- Mennatallah A. Hammam
- Matthias Engel (ORCID: https://orcid.org/0000-0001-5065-8634)
- Michal Kořínek (ORCID: https://orcid.org/0000-0002-8988-8610)
- Po-Hsiung Kung (ORCID: https://orcid.org/0000-0003-3980-2724)
- Dalia S. El‐Gamil (ORCID: https://orcid.org/0000-0002-0512-6724)
- Alireza Abadi (ORCID: https://orcid.org/0000-0002-7433-261X)
- Yu‐Cheng Chen (ORCID: https://orcid.org/0000-0002-0008-5601)
- Yi‐Hsuan Wang (ORCID: https://orcid.org/0000-0001-7194-1885)
Institutions
- Ain Shams University (EG)
- Ming Chi University of Technology (TW)
- Chang Gung University of Science and Technology (TW)
- Kaohsiung Medical University (TW)
- Chang Gung University (TW)
- Chang Gung Memorial Hospital (TW)
- Ahram Canadian University (EG)
- Saarland University (DE)
- German University in Cairo (EG)
Publication Details
- Journal
- Journal of Enzyme Inhibition and Medicinal Chemistry
- Published
- 2024-09-19
- DOI
- https://doi.org/10.1080/14756366.2024.2402988
- Citations
- 1
- Primary Topic
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.24
Funders
- Chang Gung Memorial Hospital
- Kaohsiung Medical University
- National Science and Technology Council