Development of N-hydroxycinnamamide-based HDAC inhibitors with improved HDAC inhibitory activity and in vitro antitumor activity

[Display omitted] •A novel series of N-hydroxycinnamamide-based HDAC inhibitors were synthesized.•Most compounds showed superior HDAC inhibition and antiproliferative activity.•These new compounds seem to be pan-HDAC inhibitors as parent compound 1 and SAHA. Histone deacetylase inhibitors (HDACIs) are promising in the treatment of various diseases, among which cancer treatment has achieved the most success. We have previously developed series of HDACIs combining N-hydroxycinnamamide bioactive fragment and indole bioactive fragment, which showed moderate to potent antitumor activities. Herein, further structural derivatization based on our previous structure-activity relationship (SAR) got 25 novel compounds. Most compounds showed much more potent histone deacetylases (HDACs) inhibitory activity than their parent compound 1 and even the positive control SAHA. What’s more, compared with the approved HDACs inhibitor SAHA, compounds 6i, 6k, 6q and 6t displayed better in vitro antiproliferation against multiple tumor cell lines. It is worth noting that though the 4-hydroxycinnamic acid-based compound 2 showed HDAC1/3 dual selectivity, its 4-hydroxy-3-methoxycinnamic acid-based analog 6t turned out to be a pan-HDACs inhibitor as SAHA, indicating that the 3-methoxy group on the N-hydroxycinnamamide fragment could dramatically influence the HDACs isoform selectivity of this series of compounds.