Discovery of 1,3-disubstituted prop-2-en-1-one derivatives as inhibitors of neutrophilic inflammation via modulation of MAPK and Akt pathways

Mohammad Abdel-Halim; Dalia S El-Gamil; Mennatallah A Hammam; Mohamed El-Shazly; Yi-Hsuan Wang; Po-Hsiung Kung; Yu-Cheng Chen; Michal Korinek; Ashraf H Abadi; Matthias Engel; Tsong-Long Hwang

doi:10.1080/14756366.2024.2402988

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. 2024 Dec;39(1):2402988. doi: 10.1080/14756366.2024.2402988. Epub 2024 Sep 19.

Authors

Mohammad Abdel-Halim¹, Dalia S El-Gamil², Mennatallah A Hammam³, Mohamed El-Shazly⁴, Yi-Hsuan Wang⁵, Po-Hsiung Kung^{5

6}, Yu-Cheng Chen⁶, Michal Korinek⁷, Ashraf H Abadi¹, Matthias Engel⁸, Tsong-Long Hwang^{5

6

9

10}

Affiliations

¹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt.
² Department of Chemistry, Faculty of Pharmacy, Ahram Canadian University, Cairo, Egypt.
³ School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, Cairo, Egypt.
⁴ Department of Pharmacognosy, Faculty of Pharmacy, Ain-Shams University, Cairo, Egypt.
⁵ Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
⁶ Graduate Institute of Healthy Industry Technology, Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan.
⁷ Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁸ Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbrücken, Germany.
⁹ Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
¹⁰ Department of Chemical Engineering, Ming Chi University of Technology, New Taipei City, Taiwan.

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.

Keywords: Enone derivatives; elastase; human neutrophils; inflammation; superoxide.

MeSH terms

Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
Dose-Response Relationship, Drug*
Drug Discovery
Humans
Inflammation* / drug therapy
Inflammation* / metabolism
Mitogen-Activated Protein Kinases / antagonists & inhibitors
Mitogen-Activated Protein Kinases / metabolism
Molecular Structure
Neutrophils* / drug effects
Neutrophils* / metabolism
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins c-akt* / antagonists & inhibitors
Proto-Oncogene Proteins c-akt* / metabolism
Structure-Activity Relationship

Substances

Proto-Oncogene Proteins c-akt
Mitogen-Activated Protein Kinases
Protein Kinase Inhibitors
Anti-Inflammatory Agents, Non-Steroidal

Grants and funding

This research was supported by grants from the National Science and Technology Council (NSTC 113-2321-B-255-001, 113-2321-B-182-003, 113-2320-B-037-023, 112-2321-B-182-003, 112-2321-B-255-001, 112-2320-B-037-012, 111-2320-B-255-006-MY3, 111-2321-B-255-001, and 111-2320-B-037-007), Chang Gung University of Science and Technology (ZRRPF3L0091 and ZRRPF3N0101), Chang Gung Memorial Hospital (CMRPF1P0051-3, CMRPF1P0071-3), and Kaohsiung Medical University Research Foundation (KMU-Q113011), Taiwan.