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 unique tautomerase enzymatic activity that has relevance concerning its multiple functions and small molecule inhibitors have been proven to block effects. Here we demonstrate some of the E-2-arylmethylene-1-tetralones their heteroanalogues efficiently bind MIF’s active site inhibit tautomeric (enolase, ketolase activity) functions. A set synthesised derivatives, namely compounds (4), (23), (24), (26) (32), reduced inflammatory macrophage activation. Two selected (24) (26), however, markedly inhibited ROS nitrite production, NF-κB activation, TNF-α, IL-6 CCL-2 expression. Pre-treatment mice with compound exaggerated hypothermic response high dose bacterial endotoxin. Our experiments suggest tetralones derivatives regulate activation thermal changes severe forms systemic inflammation.