Objective To design and synthesize a series of novel matrine derivatives and to investigate their in vitro anti-inflammation activities. Methods Ten novel matrine analogues were synthesized via thiosulfate reaction and classical Michael addition using sophocarpine as the starting material. The effects of all the analogues on TNF-α production and NF-κB transcriptional activity were evaluated in vitro. Results The synthesized compounds were confirmed correct by ¹HNMR and ESI-MS. Biological studies showed that the synthetic derivatives had inhibitory effects against TNF-α production and NF-κB transcriptional activity. Compound 1f had the strongest inhibitory effect against TNF-α production, with an IC₅₀ value of 9.4 μmol/L. Conclusion Introduction of liner small substitutes at the 13-position of matrine can enhance its anti-inflammatory activity.