Tetralone derivatives are MIF tautomerase inhibitors and attenuate macrophage activation and amplify the hypothermic response in endotoxemic mice
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 effec...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2021-01-01
|
| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/14756366.2021.1916010 |
| _version_ | 1818954296455069696 |
|---|---|
| author | János Garai Marcell Krekó László Őrfi Péter Balázs Jakus Zoltán Rumbus Patrik Kéringer András Garami Eszter Vámos Dominika Kovács Viola Bagóné Vántus Balázs Radnai Tamás Lóránd |
| author_facet | János Garai Marcell Krekó László Őrfi Péter Balázs Jakus Zoltán Rumbus Patrik Kéringer András Garami Eszter Vámos Dominika Kovács Viola Bagóné Vántus Balázs Radnai Tamás Lóránd |
| author_sort | János Garai |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T10:19:55Z |
| format | Article |
| id | doaj.art-99c9586e388a44fd96582e44a894d6e8 |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2024-12-20T10:19:55Z |
| publishDate | 2021-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-99c9586e388a44fd96582e44a894d6e82022-12-21T19:43:56ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742021-01-013611356136810.1080/14756366.2021.19160101916010Tetralone derivatives are MIF tautomerase inhibitors and attenuate macrophage activation and amplify the hypothermic response in endotoxemic miceJános Garai0Marcell Krekó1László Őrfi2Péter Balázs Jakus3Zoltán Rumbus4Patrik Kéringer5András Garami6Eszter Vámos7Dominika Kovács8Viola Bagóné Vántus9Balázs Radnai10Tamás Lóránd11Department of Pathophysiology, Institute for Translational Medicine, University of Pécs, Medical SchoolDepartment of Pharmaceutical Chemistry, Semmelweis UniversityDepartment of Pharmaceutical Chemistry, Semmelweis UniversityDepartment of Biochemistry and Medical Chemistry, University of Pécs, Medical SchoolDepartment of Thermophysiology, Institute for Translational Medicine, University of Pécs, Medical SchoolDepartment of Thermophysiology, Institute for Translational Medicine, University of Pécs, Medical SchoolDepartment of Thermophysiology, Institute for Translational Medicine, University of Pécs, Medical SchoolDepartment of Biochemistry and Medical Chemistry, University of Pécs, Medical SchoolDepartment of Biochemistry and Medical Chemistry, University of Pécs, Medical SchoolDepartment of Biochemistry and Medical Chemistry, University of Pécs, Medical SchoolDepartment of Biochemistry and Medical Chemistry, University of Pécs, Medical SchoolDepartment of Biochemistry and Medical Chemistry, University of Pécs, Medical SchoolMacrophage 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.http://dx.doi.org/10.1080/14756366.2021.1916010mifmif inhibitors2-arylmethylene-1-tetralonestautomeraseinflammation |
| spellingShingle | János Garai Marcell Krekó László Őrfi Péter Balázs Jakus Zoltán Rumbus Patrik Kéringer András Garami Eszter Vámos Dominika Kovács Viola Bagóné Vántus Balázs Radnai Tamás Lóránd Tetralone derivatives are MIF tautomerase inhibitors and attenuate macrophage activation and amplify the hypothermic response in endotoxemic mice Journal of Enzyme Inhibition and Medicinal Chemistry mif mif inhibitors 2-arylmethylene-1-tetralones tautomerase inflammation |
| title | Tetralone derivatives are MIF tautomerase inhibitors and attenuate macrophage activation and amplify the hypothermic response in endotoxemic mice |
| title_full | Tetralone derivatives are MIF tautomerase inhibitors and attenuate macrophage activation and amplify the hypothermic response in endotoxemic mice |
| title_fullStr | Tetralone derivatives are MIF tautomerase inhibitors and attenuate macrophage activation and amplify the hypothermic response in endotoxemic mice |
| title_full_unstemmed | Tetralone derivatives are MIF tautomerase inhibitors and attenuate macrophage activation and amplify the hypothermic response in endotoxemic mice |
| title_short | Tetralone derivatives are MIF tautomerase inhibitors and attenuate macrophage activation and amplify the hypothermic response in endotoxemic mice |
| title_sort | tetralone derivatives are mif tautomerase inhibitors and attenuate macrophage activation and amplify the hypothermic response in endotoxemic mice |
| topic | mif mif inhibitors 2-arylmethylene-1-tetralones tautomerase inflammation |
| url | http://dx.doi.org/10.1080/14756366.2021.1916010 |
| work_keys_str_mv | AT janosgarai tetralonederivativesaremiftautomeraseinhibitorsandattenuatemacrophageactivationandamplifythehypothermicresponseinendotoxemicmice AT marcellkreko tetralonederivativesaremiftautomeraseinhibitorsandattenuatemacrophageactivationandamplifythehypothermicresponseinendotoxemicmice AT laszloorfi tetralonederivativesaremiftautomeraseinhibitorsandattenuatemacrophageactivationandamplifythehypothermicresponseinendotoxemicmice AT peterbalazsjakus tetralonederivativesaremiftautomeraseinhibitorsandattenuatemacrophageactivationandamplifythehypothermicresponseinendotoxemicmice AT zoltanrumbus tetralonederivativesaremiftautomeraseinhibitorsandattenuatemacrophageactivationandamplifythehypothermicresponseinendotoxemicmice AT patrikkeringer tetralonederivativesaremiftautomeraseinhibitorsandattenuatemacrophageactivationandamplifythehypothermicresponseinendotoxemicmice AT andrasgarami tetralonederivativesaremiftautomeraseinhibitorsandattenuatemacrophageactivationandamplifythehypothermicresponseinendotoxemicmice AT esztervamos tetralonederivativesaremiftautomeraseinhibitorsandattenuatemacrophageactivationandamplifythehypothermicresponseinendotoxemicmice AT dominikakovacs tetralonederivativesaremiftautomeraseinhibitorsandattenuatemacrophageactivationandamplifythehypothermicresponseinendotoxemicmice AT violabagonevantus tetralonederivativesaremiftautomeraseinhibitorsandattenuatemacrophageactivationandamplifythehypothermicresponseinendotoxemicmice AT balazsradnai tetralonederivativesaremiftautomeraseinhibitorsandattenuatemacrophageactivationandamplifythehypothermicresponseinendotoxemicmice AT tamaslorand tetralonederivativesaremiftautomeraseinhibitorsandattenuatemacrophageactivationandamplifythehypothermicresponseinendotoxemicmice |