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.

PurposeThe purpose of this study was to design and synthesize novel 2-benzylidene-1-indanone derivatives for treatment of acute lung injury.MethodsA series of 39 novel 2-benzylidene-indanone structural derivatives were synthesized and evaluated for anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated murine primary macrophages.ResultsMost of the obtained compounds effectively inhibited the LPS-induced expression of IL-6 and TNF-α. The most active compound, 8f, was found to significantly reduce LPS-induced pulmonary inflammation, as reflected by reductions in the concentration of total protein, inflammatory cell count, as well as the lung wet/dry ratio in bronchoalveolar lavage (BAL) fluid. Furthermore, 8f effectively inhibited mRNA expression of several inflammatory cytokines after LPS challenge in vitro and in vivo. Administration of 8f also blocked LPS-induced activation of the proinflammatory NF-κB/MAPK signaling pathway.ConclusionThe simple synthetic preparation and biological properties of these derivatives make these 2-benzylidene-indanone scaffolds promising new entities for the development of anti-inflammatory therapeutics for the treatment of acute lung injury.

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The front cover picture shows a series of newly discovered compounds with high inhibitory activities against lipopolysaccharide (LPS)‐induced cytokine expression. By performing systematic structure–activity relationship (SAR) studies of the lead compound, two thiazolo[3,2‐a]pyrimidine analogues (11e and 11l) were identified as the most potent anti‐inflammatory compounds. Pretreatment with them in vivo potently decreased the cytokine levels in bronchoalveolar lavage fluid and improved the histopathological changes of the lung in LPS‐stimulated acute lung injury (ALI) mice. These results provide potential anti‐inflammatory candidates for the treatment of ALI and sepsis. More information can be found in the Full Paper by Guang Liang et al. on page 1022 in Issue 13, 2017 (DOI: 10.1002/cmdc.201700175).