Structure-Based Drug Design and Synthesis of Pyrrolidine-2,5-diones as Novel TNF-α Inhibitors

Abstract

Tumor necrosis factor α (TNF-α) inhibitors are the treatment of choice for autoimmune diseases including rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and Crohn’s disease. Herein, some Benpyrine derivatives with stronger binding affinity, better activity, better solubility, and higher synthetic efficiency were identified using structure-based drug design and optimization strategies. Among the synthesized series of compounds, 10 directly binds to TNF-α and blocks the activation of TNF-α-trigged caspase and NF-κB signaling pathway. Compound 10 represents a promising scaffold for the further development of TNF-α inhibitors. Drug development based on compound 10 may provide a new strategy for the treatment of TNF-α-mediated autoimmune diseases.