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

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.