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

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with enzymatic activities. Antiinflammatory 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 mu mol/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, TNF alpha and IL-6 production in lipopolysaccharideinduced macrophages. Compound 20, 37 and 61 also inhibited ROS generation, and compound 26 and 37 abolished activation of NF-kappa B. 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.

Automated summary

This study reports the synthesis, docking, and bioactivity of substituted benzylidene-1-indanone and -1-tetralone derivatives as MIF-tautomerase inhibitors. Many of these derivatives were effective inhibitors of MIF-tautomerase, with 1-indanone derivatives 16 and 20 being the most potent. Some compounds also acted as selective enolase or ketonase inhibitors. Additionally, several compounds exhibited anti-inflammatory effects and inhibited the production of NO, TNF alpha, and IL-6 in lipopolysaccharide-induced macrophages.