Utilization of tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinone as a cap moiety in design of novel histone deacetylase inhibitors

[Display omitted] •12 novel compounds contain Tetrahydrobenzo[4,5]Thieno[2,3-d]pyrimidinone as a novel cap group, attached to ZBG via aliphatic, aralkyl or aromatic linker was designed and synthesized.•The synthesized hybrids were evaluated for their HDAC inhibitory and in vitro cytotoxic activities against different human cancer cell lines.•Compounds IVa, IVb, IXa and IXb showed potent HDAC inhibitory activity.•Compounds IVb and IXb were selected for cell cycle analysis and apoptosis assay.•Molecular modeling for compounds IVb and IXb were done against 3D crystal structures of HDAC2. A series of novel 5,6,7,8-Tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-one derivatives bearing a hydroxamic acid, 2-aminoanilide and hydrazide moieties as zinc-binding group (ZBG) were designed, synthesized and evaluated for the HDAC inhibition activity and antiproliferative activity. Most of the tested compounds displayed strong to moderate HDAC inhibitory activity. Some of these compounds showed potent anti-proliferative activity against human HepG2, MCF-7 and HCT-116 cell lines. In particular, compounds IVa, IVb, IXa and IXb exhibited significant anti-proliferative activity against the three cell lines tested compared to SAHA as a reference. Compound IVb is equipotent inhibitor for HDAC1 and HDAC2 as SAHA. It is evident that the presence of free hydroxamic acid group is essential for Zn binding affinity with maximal activity with a linker of aliphatic 6 carbons. Docking study results revealed that compound IVb could occupy the HDAC2 binding site and had the potential to exhibit antitumor activity through HDAC inhibition, which merits further investigation.