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

Abstract

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, <b>4j, 5c</b>, and <b>5e</b> displayed effective inhibitions for Aβ self-aggregation, HDAC5 activity and HDAC7 activity with IC₅₀ values of <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_1-42. Furthermore, compounds <b>4j, 5c</b>, and <b>5e</b> showed no significant cytotoxicity to human neuroblastoma SH-SY5Y cells and also exhibited neuroprotective effect against H₂O₂-induced toxicity. Overall, these promising <i>in vitro</i> data highlighted compounds <b>4j, 5c</b>, and <b>5e</b> as lead compounds that are worthy for further investigation.