As a part of an ongoing effort to find alternate chemotherapeutic agents for hepatocellular carcinoma, we herein, report the design and synthesis of two novel compounds targeting histone deacetylase (HDAC) with 2,4-thiazolidinedione as zinc chelating group. Further, we demonstrate that these compounds show cytotoxicity that parallels their ability to inhibit HDACs activity in human liver cancer cell line HepG2. The findings obtained in this study indicate that 2,4-thiazolidinedione group may be utilized successfully to inhibit HDAC activity with future potential for lead optimization by chemical derivatization of active compound, N-(6-(2,4-dioxothiazolidin-3-yl)hexyl) benzenesulfonamide.