Abstract: Urushiol was used as raw material, through etherification of o-diphenol hydroxyl group, introducing isoxamic acid group into the tail of side chain, and functional groups of nitro, hydroxyl group into benzene ring or aliphatic chain. Three novel methylene ether urushiol hydroxamic acid derivatives were synthesized. The structure of the synthesized compounds was characterized by means of ¹H NMR, ¹³ C NMR and MS analysis. The interaction mode between the compounds and HDAC 2 was studied by molecular docking. The results showed that three compounds could bind to the active pocket of HDAC 2 and interact with the residues of His145, Tyr 308, Glu103 and Asp104 to form hydrogen bonds. It could form stable chelation with Zn²⁺ at the bottom of active pocket. The inhibitory activity of compounds on HDAC 2 was detected by kit AK-501. The results showed that the inhibitory effects of compound 2 and 3 on HDAC 2 were better than that of compound 1, and the IC₅₀ values of compound 2 and 3 were similar to that of SAHA(IC₅₀=0.20 mg/L), the half inhibitory concentrations (IC₅₀) of compounds 1, 2 and 3 on HDAC2 were 0.33, 0.29 and 0.24 mg/L, respectively.