Design, synthesis and biological evaluation of piperazino-enaminones as novel suppressants of pro-Inflammatory cytokines

• Published in: Bioorganic & medicinal chemistry 2018-08, Vol.26 (14), p.3890-3898
• Main Authors: Ghoneim, Ola M., Bill, Ashley, Dhuguru, Jyothi, Szollosi, Doreen E., Edafiogho, Ivan O.
• Format: Article
• Language: English
• Subjects: Aniline Compounds - chemistry; Aniline Compounds - pharmacology; Animals; Cells, Cultured; Cyclohexanecarboxylic Acids - chemistry; Cyclohexanecarboxylic Acids - pharmacology; Cytokines; Cytokines - antagonists & inhibitors; Cytokines - metabolism; Design; Dose-Response Relationship, Drug; Drug Design; Inflammation; Lipopolysaccharides - antagonists & inhibitors; Lipopolysaccharides - pharmacology; Mice; Molecular Structure; Piperazines - chemistry; Piperazines - pharmacology; Pro-inflammatory; Structure-Activity Relationship; Synthesis
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2018.06.003

[Display omitted] Infection triggers the release of pro-inflammatory cytokines (TNF-alpha and IL-6). Over-production, however, cause tissue injury seen in severe asthma. The ability of enaminone E121 to reduce pro-inflammatory cytokines in our laboratory encouraged further examination of its structural scaffold. Piperazino-enaminones were designed by incorporating n-arylpiperazine motif into the aromatic enaminone. Four possible modifications were explored systematically. Synthesis was accomplished by amination of the corresponding methyl/ethyl 2,4-dioxo-6-(substituted)cyclohexane-carboxylate.. Sixteen novel compounds were synthesized. Biological activity was tested in J774 macrophages stimulated with lipopolysaccharides. The release of cytokines was measured via ELISA. Four compounds significantly suppressed TNF-alpha and IL-6 release in dose-dependent manner.