Synthesis and Anti‐Inflammatory Activity Evaluation of Benzoxazole Derivatives as New Myeloid Differentiation Protein 2 Inhibitors

Abstract

AbstractMyeloid differentiation protein 2 (MD2), a key TLR4 adaptor protein for sensing LPS, plays an important role in inflammatory process and has been identified as a promising target for the treatment of a variety of inflammatory diseases. In our study, a series of benzoxazolone derivatives were synthesized, characterized and tested for anti‐inflammatory activity in vitro. The compounds 3c, 3d and 3g demonstrated the greatest anti‐inflammatory activity against IL‐6 with IC50 values of 10.14±0.08, 5.43±0.51 and 5.09±0.88 μM, respectively. Furthermore, the bis‐ANS displacement assay revealed that these compounds competitively inhibited the binding between the probe bis‐ANS and the MD2 protein. The most active compound 3g, revealed a directly bind with MD2 protein via Arg90 binding and a dissociation constant value of 1.52×10−6 mol L−1 as determined by the biological layer interference (BLI) assay. Our finding suggested that compounds 3g could be a promising lead compound as MD2 inhibitor for further anti‐inflammatory agent development.