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

• DOI: 10.1016/j.ejmech.2022.115050
• Publication Date: 2022-12-28T16:39:17Z
• Authors: János Garai; Balázs Radnai; Eszter Vámos; Dominika Kovács; Viola Bagóné Vántus; Zoltán Rumbus; Eszter Pákai; András Garami; Gergely Gulyás-Fe...; Attila Agócs; Marcell Krekó; Khadiza Zaman; László Prókai; László Őrfi; Péter B. Jakus; Tamás Lóránd
• Keywords: Lipopolysaccharides; Mice; 0303 health sciences; 03 medical and health sciences; Animals; Molecular Dynamics Simulation; Macrophage Migration-Inhibitory Factors; Shock, Septic; 3. Good health

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.