Synthesis and evaluation of a new class of MIF-inhibitors in activated macrophage cells and in experimental septic shock in mice

• Published in: European journal of medicinal chemistry Vol. 247; p. 115050
• Main Authors: Garai, János, Radnai, Balázs, Vámos, Eszter, Kovács, Dominika, Vántus, Viola Bagóné, Rumbus, Zoltán, Pákai, Eszter, Garami, András, Gulyás-Fekete, Gergely, Agócs, Attila, Krekó, Marcell, Zaman, Khadiza, Prókai, László, Őrfi, László, Jakus, Péter B., Lóránd, Tamás
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 05-02-2023
• Subjects: Animals; Inflammation; Lipopolysaccharides - pharmacology; Macrophage migration inhibitory factor inhibitor; Macrophage Migration-Inhibitory Factors; Mice; Molecular Dynamics Simulation; Molecular modelling; Shock, Septic - chemically induced; Shock, Septic - drug therapy; Substituted benzylidene-1-tetralones and -indan-1-ones; Thermophysiology; Substituted benzylidene-1-tetralones and -indan-1-ones; Macrophage migration inhibitory factor inhibitor; Inflammation; Molecular modelling; Thermophysiology
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2022.115050

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with enzymatic activities. Anti-inflammatory effects of MIF enzyme inhibitors indicate a link between its cytokine- and catalytic activities. Herein the synthesis, docking, and bioactivity of substituted benzylidene-1-indanone and -1-tetralone derivatives as MIF-tautomerase inhibitors is reported. Many of these substituted benzylidene-1-tetralones and -indan-1-ones were potent MIF-tautomerase inhibitors (IC50 < 10 μmol/L), and the most potent inhibitors were the 1-indanone derivatives 16 and 20. Some of these compounds acted as selective enolase or ketonase inhibitors. In addition, compounds 16, 20, 26, 37 and 61 efficiently inhibited NO, TNFα and IL-6 production in lipopolysaccharide-induced macrophages. Compound 20, 37 and 61 also inhibited ROS generation, and compound 26 and 37 abolished activation of NF-κB. Compound 37 significantly augmented hypothermia induced by high dose of lipopolysaccharide in mice. The possible mechanisms of action were explored using molecular modelling and docking, as well as molecular dynamics simulations.
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•Synthesis of substituted (E)-2-arylmethylene-1-tetralones.•The molecules bind MIF and inhibit its tautomerase activity.•Selected compounds reduce ROS, NO and cytokine production in activated macrophages.•The best inhibitor augments hypothermia in experimental septic shock in mice.