Design, Synthesis, and Structure–Activity Relationship Analysis of Thiazolo[3,2‐a]pyrimidine Derivatives with Anti‐inflammatory Activity in Acute Lung Injury

Acute lung injury (ALI) has a high lethality rate, and interleukin‐6 (IL‐6) and tumor necrosis factor‐α (TNF‐α) contribute most to tissue deterioration in cases of ALI. In this study, we designed and synthesized a new series of thiazolo[3,2‐a]pyrimidine derivatives based on a previously identified lead compound, and we evaluated their anti‐inflammatory activities. Structure–activity relationship studies led to the discovery of two highly potent inhibitors. The two promising compounds were found to inhibit lipopolysaccharide (LPS)‐induced IL‐6 and TNF‐α release in a dose‐dependent manner in mouse primary peritoneal macrophages (MPMs). Furthermore, administration of these compounds resulted in lung histopathological improvements and attenuated LPS‐induced ALI in vivo. Taken together, these data indicate that these novel thiazolo[3,2‐a]pyrimidine derivatives could be developed as candidate drugs for the treatment of ALI. Breathe easy: Based on lead compound 6, we designed and synthesized a series of thiazolo[3,2‐a]pyrimidine derivatives. The most promising compounds, 11 e and 11 l, were found to inhibit lipopolysaccharide (LPS)‐induced cytokines with IC50 values in the low‐ to sub‐micromolar range. Further administration of these compounds in mice was found to attenuate LPS‐induced acute lung injury.