Chu, Jung-ChunJung-ChunChuTseng, Hui-JuHui-JuTsengLee, Sung-BauSung-BauLeeHsu, Kai-ChengKai-ChengHsuLING-WEI HSINLiang, Ru-HaoRu-HaoLiangLin, Tony EightTony EightLinGao, Nain-ChuNain-ChuGaoChen, Liang-ChiehLiang-ChiehChenLu, Wan-HsunWan-HsunLuWang, Andrew H-JAndrew H-JWangHuang, Wei-JanWei-JanHuang2024-03-272024-03-272023-1214756366https://scholars.lib.ntu.edu.tw/handle/123456789/641457Class 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.enHistone deacetylase (HDAC); neuron cells; phenoxazine; structure-activity relationship (SAR)[SDGs]SDG3journal article10.1080/14756366.2023.2212326371909312-s2.0-85159484079https://api.elsevier.com/content/abstract/scopus_id/85159484079