Harnessing Substituted 4-Chlorothieno[2,3-b]pyridine as a New Cap for Potent and Selective Antiproliferative HDAC Inhibitors

<b>Background:</b> Inhibition of histone deacetylase is a highly sought-after objective in the fight against cancer. Thus, the development of innovative HDAC inhibitors with significantly higher potency than SAHA against specific cancer cell types represents complex and demanding work. <b>Method:</b> The utilization of the underexplored and privileged scaffold 4-chlorothieno[2,3-<i>b</i>]pyridine as a cap tethering diverse aliphatic and aromatic linkers, followed by the screening of both cellular and enzymatic activities, is undertaken in this study. <b>Results:</b> Compounds <b>7a</b> and <b>9a</b> demonstrated impressive mean GI₅₀ values of 2.15 µM and 1.89 µM, respectively. Both compounds reduced caspase-3 levels in RPMI-8226 cells, suggesting induction of apoptosis. Compound <b>7a</b> showed remarkable IC₅₀ values of 0.37 µM, 0.58 µM, and 0.70 µM against HDACs 1, 4, and 6, respectively, consistent with the cellular assay. Additionally, compound <b>7a</b> exhibited a selectivity index of 11 for RPMI-8226 cells over PBMCs, reflecting its high selectivity and potential safety. Moreover, ADMET prediction tools indicated that compounds <b>7a</b> and <b>9b</b> may have more favorable pharmacokinetic properties than the gold-standard HDAC inhibitor, SAHA. <b>Conclusions:</b> Further study and exploration of the derivatives of compounds <b>7a</b> and <b>9a</b> can lead to further advancement in the development of potent HDAC inhibitor anticancer drugs.