Myeloid differentiation 2 (MD2) is essential to the recognition of lipopolysaccharide (LPS) and the subsequent mediation of toll-like receptor 4 (TLR4)-dependent acute inflammatory disorders including sepsis and acute lung injury. Inhibitors targeting MD2 may provide an alternative means to subdue acute inflammatory diseases. In the present study, 39 bisaryl-1,4-dien-3-one compounds with 5-carbon connection chains were designed and synthesized as MD2 inhibitors based on the analysis of the molecular docking of xanthohumol to MD2. The compound-MD2 interactions were measured by cell-free assays including bis-ANS displacement and SPR, and the active compounds were further tested for MD2 inhibition and anti-inflammatory activities in LPS-challenged macrophages. The most active compound, 1f, was shown to have remarkable protective effects against sepsis shock and pulmonary inflammation. Collectively, we present evidence that bisaryl-1,4-dien-3-one is a new lead structure for the development of anti-inflammatory agents targeting MD2.

髓样分化2（MD2）对于脂多糖（LPS）的识别以及随后介导的Toll样受体4（TLR4）依赖性急性炎症（包括败血症和急性肺损伤）的介导至关重要。靶向MD2的抑制剂可提供另一种方法来制服急性炎症性疾病。在本研究中，基于对黄腐酚与MD2的分子对接分析，设计并合成了39个具有5-碳连接链的双芳基-1,4-二烯-3-酮化合物，并将其作为MD2抑制剂。通过无细胞试验（包括bis-ANS置换和SPR）测量了化合物-MD2的相互作用，并进一步测试了活性化合物在LPS攻击的巨噬细胞中对MD2的抑制作用和抗炎活性。活性最高的化合物1f证明对脓毒症休克和肺部炎症具有显着的保护作用。总的来说，我们提供的证据表明，bisaryl-1,4-dien-3-one是开发针对MD2的抗炎药的新的先导结构。