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, 4j, 5c, and 5e 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 Aβ1-42. Furthermore, compounds 4j, 5c, and 5e showed no significant cytotoxicity to human neuroblastoma SH-SY5Y cells and also exhibited neuroprotective effect against H2O2-induced toxicity. Overall, these promising in vitro data highlighted compounds 4j, 5c, and 5e as lead compounds that are worthy for further investigation.
ASJC Scopus subject areas
- Pharmacology (medical)
Chen, L. C., Tseng, H. J., Liu, C. Y., Huang, Y. Y., Yen, C. C., Weng, J. R., Lu, Y. L., Hou, W. C., Lin, T. E., Pan, I. H., Huang, K. K., Huang, W. J., & Hsu, K. C. (2018). Design of diarylheptanoid derivatives as dual inhibitors against class IIa histone deacetylase and β-amyloid aggregation. Frontiers in Pharmacology, 9(JUL), . https://doi.org/10.3389/fphar.2018.00708