AUTHOR=Chen Liang-Chieh , Tseng Hui-Ju , Liu Chang-Yi , Huang Yun-Yi , Yen Cheng-Chung , Weng Jing-Ru , Lu Yeh-Lin , Hou Wen-Chi , Lin Tony E. , Pan I-Horng , Huang Kuo-Kuei , Huang Wei-Jan , Hsu Kai-Cheng 

TITLE=Design of Diarylheptanoid Derivatives as Dual Inhibitors Against Class IIa Histone Deacetylase and β-amyloid Aggregation

JOURNAL=Frontiers in Pharmacology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2018.00708

DOI=10.3389/fphar.2018.00708

ISSN=1663-9812

ABSTRACT=<p>Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with multiple etiologies. Beta-amyloid (Aβ) self-aggregation and overexpression of class IIa histone deacetylases (HDACs) are strongly implicated with AD pathogenesis. In this study, a series of novel diarylheptanoid derivatives were designed, synthesized and evaluated for use as dual Aβ self-aggregation and class IIa HDAC inhibitors. Among these compounds, <bold>4j, 5c</bold>, and <bold>5e</bold> displayed effective inhibitions for Aβ self-aggregation, HDAC5 activity and HDAC7 activity with IC<sub>50</sub> values of &lt;10 μM. The compounds contain three common features: (1) a catechol or pyrogallol moiety, (2) a carbonyl linker and (3) an aromatic ring that can function as an HDAC cap and create hydrophobic interactions with Aβ<sub>1-42</sub>. Furthermore, compounds <bold>4j, 5c</bold>, and <bold>5e</bold> showed no significant cytotoxicity to human neuroblastoma SH-SY5Y cells and also exhibited neuroprotective effect against H<sub>2</sub>O<sub>2</sub>-induced toxicity. Overall, these promising <italic>in vitro</italic> data highlighted compounds <bold>4j, 5c</bold>, and <bold>5e</bold> as lead compounds that are worthy for further investigation.</p>