Novel quinoline-2-one derivatives as potent receptor Interacting protein kinase 1 (RIPK1) inhibitors with therapeutic activities for acute respiratory distress syndrome

As a key regulator of cellular programmed necrosis and inflammatory signaling pathways, receptor interacting protein kinase 1 (RIPK1) is closely linked to the pathogenesis and progression of acute respiratory distress syndrome (ARDS). In this study, building on hits identified from docking simulations, a series of quinoline-2-ones was designed and synthesized as a novel class of RIPK1 inhibitors. Through the optimization of the lead structure and exploration of suitable substituents, compound 2c was found to exhibit potent inhibitory activity against cellular necroptosis. Compound 2c significantly suppressed TSZ (tumor necrosis factor-alpha (TNF-α), SM-164, and benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (Z-VAD-FMK)-induced programmed necrosis in HT29 cells at a half-maximal effective concentration of 0.53 μM. Histopathological sections of mouse lung tissues demonstrated that compound 2c markedly alleviated lipopolysaccharide (LPS)-induced lung injury. Docking analysis revealed that 2c inserted into the hydrophobic pocket formed by Tyr94-Met95-Glu96. In conclusion, compound 2c exerts its anti-necroptotic activity by modulating RIPK1 function, suggesting its potential as a promising candidate for the treatment of ARDS.