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A series of novel coumarin-based hydroxamate derivatives were designed and synthesized as histone deacetylase inhibitors (HDACis). Selective compounds showed a potent HDAC inhibition with nM IC₅₀ values, with the best compound (<b>10e</b>) being nearly 90 times more active than vorinostat (SAHA) against HDAC1. Compounds <b>10e</b> and <b>11d</b> also increased the levels of acetylated histone H3 and H4, which is consistent with their strong HDAC inhibition. In addition, <b>10e</b> and <b>11d</b> displayed a higher potency toward human A549 and Hela cancer cell lines compared with SAHA. Moreover, <b>10e</b> and <b>11d</b> significantly arrested A549 cells at the G2/M phase and enhanced apoptosis. Molecular docking studies revealed the possible mode of interaction of compounds <b>10e</b> and <b>12a</b> with HDAC1. Our findings suggest that these novel coumarin-based HDAC inhibitors provide a promising scaffold for the development of new potential cancer chemotherapies.