Design, Synthesis, and Antirheumatoid Arthritis Mechanism of TLR4 Inhibitors.

A total of 12 carbonyl compounds were synthesized, their lipopolysaccharide induced inhibition, and activity of RAW264.7 cells was evaluated. The most active compound inhibited RAW264.7 cells with IC value of 1.02 ± 0.08 μM. Compound significantly inhibited the release of TNF-α, IL-1β, and IL-6 in supernatant for RAW264.7 cells. In vivo collagen-induced arthritis model tests administered orally, compound showed effects similar to those of methotrexate in the positive control group. The preliminary mechanism study showed that compound had an effect on abnormal expression for TLR4, TNF-α, NF-κB protein, and genes related to inflammation signaling pathway in RAW264.7 cells. Meanwhile, compound showed a good affinity for the TLR4 receptor in molecular docking simulation. Therefore, compound may be a promising lead compound for the treatment of rheumatoid arthritis.