Recently, histone deacetylase (HDAC) inhibition has gained great importance in cancer treatment. We herein, describe the design, synthesis and biological testing of 16 compounds based on the structure modification of methyl 3-(4-(2-chloroacetamido)phenyl)-3-hydroxy-2,2-dimethylpropanoate (5) and methyl 3-(4-chlorophenyl)-3-hydroxy-2,2-dimethylpropanoate (14) as potent HDACIs. Two series were synthesized based on the structure of 3-(4-(2-chloroacetamido)phenyl)-3-hydroxy-2,2-dimethylpropanoate and 3-(4-chlorophenyl)-3-hydroxy-2,2-dimethylpropanoate. The compounds were tested in vitro for their antiproliferative activity against HeLa cells. The results identified compounds 16b, 16c, 18 (IC₅₀; 11.69, 0.69, 3.39 μM respectively) as potential good inhibitors compared to the standard drug doxorubicin (IC₅₀; 2.29 μM). Those compounds also exhibited promising activity against other cancer cell lines namely; HCT-116, MCF-7, PC3, A549 and therefore were selected as hits for further optimization. The docking experiment results performed on the HDAC-2 crystal structure were in close agreement with the biological testing results which suggest that those compounds potentially work through HDAC inhibition.