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Design and Synthesis of Novel Isoflavene TANK-Binding Kinase 1 Inhibitors With Anti-Inflammatory Activity
Valerio Falasca1, W Samantha N Jayasekara2,3, Dominic De Nardo4
1School of Chemistry, University of New South Wales, Sydney, New South Wales, Australia.
None:
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 (IC50 = 0.13 µM), representing a 6.7-fold improvement compared to the parent isoflavene compound.
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