Targeting Receptor-Interacting Protein Kinase 1 by Novel Benzothiazole Derivatives: Treatment of Acute Lung Injury through the Necroptosis Pathway.

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) are serious and devastating pulmonary manifestations of acute systemic inflammation with high morbidity and mortality worldwide. Currently, there are no specific effective treatments for ALI/ARDS. RIPK1, which contributes to necroptosis and inflammation, is confirmed to be a promising strategy for the treatment of ALI. Herein, 23 benzothiazole derivatives were designed to specifically target RIPK1, and showed high anti-necroptotic activity (EC = 22.4 nM) and kinase selectivity on RIPK1 over RIPK3 ( = 85 nM, > 10,000 nM). In a mTNF-α-induced systemic inflammatory response syndrome (SIRS) model, could completely reverse mouse deaths with significant anti-inflammatory effects. Furthermore, in a NNK short-term intratracheal exposure-induced ALI model, significantly alleviated ALI by reducing pulmonary edema and pathological damage. Collectively, activities of against RIPK1, necroptosis, SIRS, and ALI warranted further investigation of optimized benzothiazoles as promising lead structures against ALI-related diseases.