Objective To design and synthesize a series of sinomenine derivatives and to investigate their anti-inflammation activities in vitro. Methods Nine sinomenine derivatives were synthesized via demethylate of N atom, nucleophilic substitution and classical Click Reaction using sinomenine as the starting material. The target compounds were evaluated for their influence on NF-κB transcriptional activity in vitro. Results All the synthesized compounds were reported for the first time, and they were confirmed by ¹HNMR and LC-MS. Biological studies showed that all the synthetic derivatives exhibited certain inhibitory effect against NF-κB transfection in vitro, but was weaker than that of sinomenine. Conclusion Replacing N-methyl with large group or long side chain on nitrogen atom may weaken the anti-inflammatory activity of sinomenine.