Design and Synthesis of Novel Double-Ring Conjugated Enones as Potent Anti-rheumatoid Arthritis Agents

[Image: see text] Rheumatoid arthritis (RA) is a chronic and systemic disease of inflammatory synovitis with unknown etiology. In previous studies, we found that the double-ring conjugated enone structure has anti-rheumatoid arthritis activity and could effectively inhibit the proliferation of rat synovial cells in vitro and has good anti-inflammatory activity in vivo. Herein, we further modified the structure, which was a novel double-ring conjugated enone, to study its anti-rheumatoid arthritis activity. Results showed that the most potent compound 32 could effectively inhibit the proliferation of rat synovial cells in vitro and has better anti-inflammatory activity compared with that of the positive control methotrexate, as shown by in vivo activity evaluation. More interestingly, compound 32 could effectively inhibit the increase of TNF-α, IL-1β, and IL-6 induced by LPS and regulate the expression of TLR4, MyD88, NF-κB, and IκB in the signaling pathway of TLR4/NF-κB. Our results provided a promising starting point for the development of highly effective small molecules for the treatment of RA.