Discovery of New Uracil and Thiouracil Derivatives as Potential HDAC Inhibitors.

: Histone deacetylase inhibitors (HDACIs) are a relatively new class of potential drugs for treating cancer. : Discovery of new anticancer agents targeting HDAC. : New uracil and thiouracil derivatives panels were designed and synthesized as HDAC inhibitors. The synthesized compounds were tested against MCF-7, HepG2, and HCT-116. HDAC1 and HDAC4 inhibitory activities of these compounds were tested. The most active member was tested for its potential against cell cycle, apoptosis, caspase-3, and caspase-8. Docking studies were carried out against HDAC1. : Compounds , , , , , and exhibited promising cytotoxic activities. HDAC1 and HDAC4 inhibitory activities of these compounds were tested. Regarding the HDAC1 inhibitory activity, compound was the most potent member (IC = 0.05 µg/mL) compared to trichostatin A (IC = 0.0349 µg/mL). For HDAC4, compound showed superior activity (IC = 2.83 µg/mL) than trichostatin A (IC = 3.349 µg/mL) Compound showed a high potential to arrest the HCT116 cell cycle at the G0-G1 phase. In addition, it showed an almost 17 times apoptotic effect (37.59%) compared to the control cells (2.17%). Furthermore, Compound showed significant increases in the levels of caspase-3 and caspase-8. Finally, the uracil and thiouracil derivatives showed accepted binding mods against HDAC. : Compound has potential anticancer activity targeting HDAC with a significant apoptotic effect.