Design, synthesis and biological evaluation of 2,3-dihydroimidazo[1,2-c]quinazoline derivatives as novel phosphatidylinositol 3-kinase and histone deacetylase dual inhibitorsElectronic supplementary information (ESI) available: Details of experimental procedure, spectral data of all novel compounds. See DOI: 10.1039/c7ra08835c

Histone deacetylase (HDAC) inhibitors are known to induce multiple epigenetic modifications affecting signaling networks and act synergistically with phosphatidylinositol 3-kinase (PI3K) inhibitors for the treatment of cancer. Herein we present a novel design approach for cancer drug development by incorporating HDAC inhibitory functionality into a PI3K inhibitor pharmacophore to construct dual-acting inhibitors. The designed compounds were synthesized and showed inhibitory activities against PI3K and HDAC. The representative dual PI3K/HDAC inhibitors, compounds 12a-j , showed potent antiproliferative activities against K562 and Hut78 in cellular assays. This work may lay the foundation for developing novel dual PI3K/HDAC inhibitors as potential anticancer therapeutics. A novel design approach by combination of PI3K and HDAC inhibitory activity in one molecule to produce dual inhibitors.