Discovery of quinazolinyl-containing benzamides derivatives as novel HDAC1 inhibitors with in vitro and in vivo antitumor activities

[Display omitted] •A series of novel quinazolinyl-containing benzamides derivatives were designed.•Compounds 11a selectively inhibited HDAC1 over the other HDACs isoforms.•11a inhibited proliferation of several human cancer cells.•11a had acceptable safety and oral pharmacokinetic properties.•11a showed significant antitumour activity in vivo. A series of quinazolinyl-containing benzamide derivatives were designed, synthesized and evaluated for their in vitro histone deacetylase 1 (HDAC1) inhibitory activities. Compounds 11a surpassed the known class I selective HDAC inhibitor MS-275 in both HDAC1 enzymatic inhibitory activity and cellular anti-proliferative activity against a selected set of cancer cell types (Hut78, K562, Hep3B and HCT116 cells) with no observed effects on human normal cells. In particular, compound 11a inhibited HDAC1 over the other tested HDACs isoforms (HDAC2, HDAC6 and HDAC8) with acceptable safety profiles. Moreover, compound 11a displayed favorable oral pharmacokinetic properties and showed significant antitumor activity in the A549 tumor xenograft model in vivo.