Design, Synthesis and Biological Evaluation of Piperazino-Enaminones as Novel Suppressants of Pro-Inflammatory Cytokines

Publication date: Available online 5 June 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Ola M. Ghoneim, Ashley Bill, Jyothi Dhuguru, Doreen E. Szollosi, Ivan O. Edafiogho
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.

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