Tetralone derivatives are MIF tautomerase inhibitors and attenuate macrophage activation and amplify the hypothermic response in endotoxemic mice
| Autor: | János Garai, Patrik Keringer, Marcell Krekó, László Őrfi, Balázs Radnai, Peter B. Jakus, Zoltan Rumbus, Eszter Vámos, Viola Bagone Vantus, Dominika Kovacs, András Garami, Tamás Lóránd |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Lipopolysaccharides
Male Models Molecular tautomerase medicine.medical_treatment Enolase Inflammation RM1-950 Pharmacology Systemic inflammation Mice Structure-Activity Relationship Hypothermia Induced Drug Discovery medicine Macrophage Animals Macrophage Migration-Inhibitory Factors MIF inhibitors Cells Cultured Tetralones chemistry.chemical_classification Dose-Response Relationship Drug Molecular Structure Chemistry MIF General Medicine Macrophage Activation Small molecule Mice Inbred C57BL Enzyme Cytokine RAW 264.7 Cells inflammation 2-arylmethylene-1-tetralones Macrophage migration inhibitory factor Therapeutics. Pharmacology medicine.symptom Research Article Research Paper |
| Zdroj: | Journal of Enzyme Inhibition and Medicinal Chemistry article-version (VoR) Version of Record Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 36, Iss 1, Pp 1356-1368 (2021) |
| ISSN: | 1475-6374 1475-6366 |
| Popis: | Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine playing crucial role in immunity. MIF exerts a unique tautomerase enzymatic activity that has relevance concerning its multiple functions and its small molecule inhibitors have been proven to block its pro-inflammatory effects. Here we demonstrate that some of the E-2-arylmethylene-1-tetralones and their heteroanalogues efficiently bind to MIF’s active site and inhibit MIF tautomeric (enolase, ketolase activity) functions. A small set of the synthesised derivatives, namely compounds (4), (23), (24), (26) and (32), reduced inflammatory macrophage activation. Two of the selected compounds (24) and (26), however, markedly inhibited ROS and nitrite production, NF-κB activation, TNF-α, IL-6 and CCL-2 cytokine expression. Pre-treatment of mice with compound (24) exaggerated the hypothermic response to high dose of bacterial endotoxin. Our experiments suggest that tetralones and their derivatives inhibit MIF’s tautomeric functions and regulate macrophage activation and thermal changes in severe forms of systemic inflammation. |
| Databáze: | OpenAIRE |
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