Design and Synthesis of Novel Uracil-Linked Schiff Bases As Dual Histone Deacetylase Type II/topoisomerase Type I Inhibitors With Apoptotic Potential

Abstract

<b>Aim:</b> 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. <b>Materials & methods:</b> We report the design and synthesis of a smarter novel set of uracil-linked Schiff bases (<b>19-30</b>) 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 <i>BAX</i> and antiapoptotic <i>BCL2</i> genes, molecular docking studies, and absorption, distribution, metabolism and excretion studies were conducted. <b>Results:</b> Compounds <b>22, 25</b> and <b>30</b> exhibited significant activities. The bromophenyl derivative <b>22</b> displayed the best selectivity index, with IC₅₀ values against HDAC II and Topo I of 1.12 and 13.44 μM, respectively. <b>Conclusion:</b> Compound <b>22</b> could be considered a lead HDAC II/Topo I inhibitor.