Design and synthesis of novel uracil-linked Schiff bases as dual histone deacetylase type II/topoisomerase type I inhibitors with apoptotic potential.

The previously reported dual histone deacetylase type II (HDAC II) / topoisomerase type I (Topo I) inhibitors suffer pharmacokinetic limitations because of their huge molecular weights. We report the design and synthesis of a smarter novel set of uracil-linked Schiff bases () as dual HDAC II/Topo I inhibitors keeping the essential pharmacophoric features. Cytotoxicity of all compounds was assessed against three cancer cell lines. Studies of their effects on the apoptotic and antiapoptotic genes, molecular docking studies, and absorption, distribution, metabolism and excretion studies were conducted. Compounds and exhibited significant activities. The bromophenyl derivative displayed the best selectivity index, with IC values against HDAC II and Topo I of 1.12 and 13.44 μM, respectively. Compound could be considered a lead HDAC II/Topo I inhibitor.