2-Morpholino-substituted imidazothiadiazole TAK1 inhibitors for reduction of proinflammatory cytokines

Protein kinases regulate critical cellular processes through phosphorylation, and their dysregulation is implicated in inflammatory disorders and autoimmune diseases. Transforming growth factor-β–activated kinase 1 (TAK1), a serine/threonine kinase, mediates the activation of MAPK and NF-κB signaling pathways, which leads to production of various proinflammatory cytokines and regulates immune response. Despite its central role, no selective TAK1 inhibitor has advanced to clinical use. In this study, we describe the design, synthesis, and biological evaluation of novel imidazo[2,1-b][1,3,4]thiadiazole derivatives as TAK1 inhibitors. Structural optimization, particularly C3 substitution on the indazole ring and C2 morpholine modification on the thiadiazole scaffold, yielded potent analogs. Lead compounds 7b and 27a demonstrated superior inhibition of TAK1 enzymatic activity compared to the known inhibitors Takinib. In macrophage models, 7b and 27a suppressed proinflammatory cytokines, TNF-α with IC 50 values of 0.08 μM and 0.101 μM, and IL-6 with IC 50 values of 0.102 μM and 0.141 μM, respectively, outperforming HS-276 (IC 50 = 1.7 μM for TNF-α and 2.6 μM for IL-6). These results highlight imidazothiadiazole-based TAK1 inhibitors as potential candidates for the development of anti-inflammatory therapeutics. • Imidazo[2,1-b][1,3,4]thiadiazole derivatives inhibit TAK1 phosphorylation in cells • Novel Tak1 inhibitors facilely synthesized via Suzuki coupling • In THP-1, 7b suppressed TNF-α with IC 50 values of 0.08 μM • In THP-1, 7b suppressed IL-6 with IC 50 values of 0.10 μM • Control compound suppressed TNF-α and IL-6 with IC 50 values of 1.7 μM and 2.6 μM