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

Background : Histone deacetylase inhibitors (HDACIs) are a relatively new class of potential drugs for treating cancer. Aim : Discovery of new anticancer agents targeting HDAC. Methods : 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. Results : Compounds 5a , 5b , 5f , 5i , 5k , and 5m exhibited promising cytotoxic activities. HDAC1 and HDAC4 inhibitory activities of these compounds were tested. Regarding the HDAC1 inhibitory activity, compound 5m was the most potent member (IC 50 = 0.05 µg/mL) compared to trichostatin A (IC 50 = 0.0349 µg/mL). For HDAC4, compound 5m showed superior activity (IC 50 = 2.83 µg/mL) than trichostatin A (IC 50 = 3.349 µg/mL) . Compound 5m 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 5m showed significant increases in the levels of caspase-3 and caspase-8. Finally, the uracil and thiouracil derivatives showed accepted binding mods against HDAC. Conclusions : Compound 5m has potential anticancer activity targeting HDAC with a significant apoptotic effect.