Epigenetic alterations found in all human cancers are promising targets for anticancer
therapy. In this sense, histone deacetylase inhibitors (HDACIs) are interesting anticancer agents
that play an important role in the epigenetic regulation of cancer cells. Here, we report 15 novel
hydroxamic acid-based histone deacetylase inhibitors with quinazolinone core structures. Five compounds exhibited antiproliferative activity with IC50 values of 3.4–37.8 µM. Compound 8 with a
2-mercaptoquinazolinone cap moiety displayed the highest antiproliferative efficacy against MCF-7
cells. For the HDAC6 target selectivity study, compound 8 displayed an IC50 value of 2.3 µM, which is
29.3 times higher than those of HDAC3, HDAC4, HDAC8, and HDAC11. Western blot assay proved
that compound 8 strongly inhibited tubulin acetylation, a substrate of HDAC6. Compound 8 also displayed stronger inhibition activity against HDAC11 than the control drug Belinostat. The inhibitory
mechanism of action of compound 8 on HDAC enzymes was then explored using molecular docking
study. The data revealed a high binding affinity (-7.92 kcal/mol) of compound 8 toward HDAC6.
In addition, dock pose analysis also proved that compound 8 might serve as a potent inhibitor of
HDAC11.