The search for newer histone deacetylase (HDAC) inhibitors has attracted a great deal of
interest of medicinal chemists worldwide, especially after the first HDAC inhibitor (Zolinza®, widely
known as SAHA or Suberoylanilide hydroxamic acid) was approved by the FDA for the treatment of Tcell
lymphoma in 2006. As a continuity of our ongoing research in this area, we designed and synthesized
a series of 5-aryl-1,3,4-thiadiazole-based hydroxamic acids as analogues of SAHA and evaluated their
biological activities. Most of the compounds in this series, e.g. compounds with 5-aryl moiety being 2-
furfuryl (5a), 5-bromofuran-2-yl (5b), 5-methylfuran-2-yl (5c), thiophen-2-yl (5d), 5-methylthiophen-2-yl
(5f) and pyridyl (5g-i), were found to have potent anticancer cytotoxicity with IC50 values of generally 5-
to 10-fold lower than that of SAHA in 4 human cancer cell lines assayed. Those compounds with potent
cytotoxicity were also found to have strong HDAC inhibition effects. Docking studies revealed that
compounds 5a and 5d displayed high affinities towards HDAC2 and 8.
Keywords: Histone deacetylase (HDAC) inhibitors, 5-aryl-1, 3, 4-thiadiazole, cytotoxicity, heterocycle.
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