Design and synthesis of novel Hydroxamate and non-Hydroxamate HDAC inhibitors based on Chromone and Quinazolone scaffolds

Abstract

The development of selective histone deacetylase (HDAC) inhibitors represents an encouraging approach for cancer therapy. In this study, we report design, synthesis, and biological evaluation of hydroxamate, amidoxime, and carboxylic acid-based derivatives as novel HDAC inhibitors. The synthesized compounds were assessed for their inhibitory activity against multiple HDAC isoforms, particularly HDAC6, 7, and 8. Compounds 13, 16, 20, and 26 exhibited potent and selective inhibition of HDAC6. Compound 26 exhibited the most potent inhibitory activity against HDAC6, with an IC₅₀ value of 70 nM. Additionally, compounds 17 and 23 demonstrated significant broad-spectrum antiproliferative activity across various cancer cell lines compared to other tested derivatives. Furthermore, compounds 17 and 23 showed promising total pan-HDAC inhibitory activity. Subsequent biological studies revealed that compounds 13, 16, 17, 20, 23, and 26 induced a combination of early and late apoptosis along with necrosis. In silico studies, including molecular docking and ADME predictions, were also conducted. Collectively, these findings highlight the potential of these compounds as promising candidates for the development of a novel class of selective HDAC6 inhibitors in the future.