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

[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 structu...

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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
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Summary:[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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2018.06.003