Design and Synthesis of Novel Isoflavene TANK‐Binding Kinase 1 Inhibitors With Anti‐Inflammatory Activity

Chronic inflammation accounts for more than half of all global deaths, and is associated with many diseases including cancer, heart disease or diabetes. Here a novel series of TANK‐binding kinase 1 (TBK1) inhibitors based on isoflavonoid derivatives was synthesised via the multicomponent Petasis reaction. TBK1 is a key mediator of several inflammatory pathways, and its inhibition shows great promise for overcoming autoimmune diseases, hyper‐inflammatory diseases, neurodegenerative diseases, and cancer resistance. Molecular modelling and SAR studies were conducted on isoflavonoid derivatives with established anti‐inflammatory activity to generate a library of novel analogues with improved biological activity. A series of TBK1 inhibitors were synthesised, with the lead compound 7a exhibiting potent inhibitory activity against NF‐κB and type I IFN inflammatory signalling pathways (IC 50 = 0.13 µM), representing a 6.7‐fold improvement compared to the parent isoflavene compound.