During the discovery of histone deacetylase inhibitors (HDACIs) as antitumor drugs, a series of potent phenylglycine-based HDACIs were developed. However, further development is restricted by the poor solubility. Therefore, structural modifications were performed in the present study in the development of potent HDACIs with improved pharmacokinetic properties. The synthesized molecules were designed by the substitution of fatty linkers for aromatic linkers, and showed good solubility profiles. Among the compounds derived, molecule HD9 showed a potent enzyme-inhibitory effect (IC50 values of 76 nmol/l) and in-vitro antiproliferative activities (IC50 values of 0.51, 0.83, and 0.76 µmol/l against U937, K562, and HL60 cells, respectively). Molecule HD9 showed selectivity of HDAC3 over HDAC6 in the isoform selectivity assays. Molecular docking studies showed good binding patterns of molecule HD9 to the active site of HDAC3. Results from the present work indicated that molecule HD9 is a promising lead compound for the tumor therapy.