Histone deacetylases (HDACs) play an important role in tumorigenesis. Inhibition of HDACs is considered as a potent strategy for cancer therapy. Two lead compounds (ja and jb) were found to have activities against HDACs with IC50 at about 15 μmol/L. Then a new series of hydroximic acid derivatives were designed and synthesized based on them. The HDACs activity assay in vitro found that compounds J04 and J09 are nearly as potent as the positive control drug Zolinza.