Discovery of a novel pyrimidine derivative for treatment of acute lung injury through reducing oxidative stress and inflammatory response

Abstract

Acute lung injury (ALI) is a multifactorial respiratory disease characterized by uncontrolled inflammatory response and has high morbidity and mortality. There is currently a lack of effective drugs for ALI treatment. In this study, through nitric oxide (NO) release inhibition and cytotoxicity screening from the in-house compound library, hit compound 6 was discovered. Using 2,4,5-trichloropyrimidine as raw material, 27 new molecules were rapidly synthesized as modified products of compound 6 through nucleophilic substitution reaction and Buchwald–Hartwig reaction. Further activity evaluation and structure–activity relationship study confirmed that compound 32 was a low-toxicity, highly efficient lead compound. Action mechanism studies indicated that compound 32 can significantly reduce the inflammatory response induced by lipopolysaccharide (LPS) in RAW264.7 cells, manifested by the down-regulation of the levels of cytokines, reactive oxygen species (ROS), and the protein expression of Toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) and Kelch-like ECH-associated protein-1/nuclear factor-erythroid 2-related factor 2/heme oxygenase-1 (Keap1-NRF2-HO-1). An in vivo anti-inflammatory study showed that it can reduce the severity of lung injury in the ALI model, accompanied by a reduction in the levels of inflammatory factors and related protein expression levels.