Synthesis and biological evaluation of C-4 substituted phenoxazine-bearing hydroxamic acids with potent class II histone deacetylase inhibitory activities

Abstract

Class II histone deacetylases (HDACs) are considered as potential targets to treat Alzheimer’s disease (AD). Previously, C-3 substituted phenothiazine-containing compounds with class II HDAC-inhibiting activities was found to promote neurite outgrowth. This study replaced phenothiazine moiety with phenoxazine that contains many C-3 and C-4 substituents. Some resulting compounds bearing the C-4 substituent on a phenoxazine ring displayed potent class II HDAC inhibitory activities. Structure-activity relationship (SAR) of these compounds that inhibited HDAC isoenzymes was disclosed. Molecular modelling analysis demonstrates that the potent activities of C-4 substituted compounds probably arise from π-π stacked interactions between these compounds and class IIa HDAC enzymes. One of these, compound 7d exhibited the most potent class II HDAC inhibition (IC₅₀= 3–870 nM). Notably, it protected neuron cells from H₂O₂-induced neuron damage at sub-μM concentrations, but with no significant cytotoxicity. These findings show that compound 7d is a lead compound for further development of anti-neurodegenerative agents.

Keywords:

• Histone deacetylase (HDAC)
• phenoxazine
• structure-activity relationship (SAR)
• neuron cells

Acknowledgements

We gratefully acknowledge the support from the National Science and Technology Council (MOST111-2320-B-038–042-MY3 and MOST110-2320-B-038–024-MY3) in Taiwan.

Disclosure statement

The authors report no conflicts of interest.

Additional information

Funding

This work was supported by the Ministry of Science and Technology, Taiwan.