Synthesis, bioevaluation and docking study of 5-substitutedphenyl-1,3,4-thiadiazole-based hydroxamic acids as histone deacetylase inhibitors and antitumor agents

Since the first histone deacetylase (HDAC) inhibitor (Zolinza (R), widely known as suberoylanilide hydroxamic acid; SAHA) was approved by the Food and Drug Administration for the treatment of T-cell lymphoma in 2006, the search for newer HDAC inhibitors has attracted a great deal of interest of medicinal chemists worldwide. As a continuity of our ongoing research in this area, we designed and synthesized a series of 5-substitutedphenyl-1,3,4-thiadiazole-based hydroxamic acids as analogues of SAHA and evaluated their biological activities. A number of compounds in this series, for example, N-1-hydroxy-N (8)-(5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl)octandiamide (5b), N-1-hydroxy-N-8-(5-(3-chlorophenyl-1,3,4-thiadiazol-2-yl)octandiamide (5c) and N-1-hydroxy-N-8-(5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl)octandiamide (5d), were found to possess potent anticancer cytotoxicity and HDAC inhibition effects. Compounds 5b-d were generally two-to five-fold more potent in terms of cytotoxicity compared to SAHA against five cancer cell lines tested. Docking studies revealed that these hydroxamic acid displayed higher affinities than SAHA toward HDAC8.