Synthesis and biological evaluation of acridine-based histone deacetylase inhibitors as multitarget agents against Alzheimer's disease.
Eur J Med Chem
; 192: 112193, 2020 Apr 15.
Article
in En
| MEDLINE
| ID: mdl-32151835
ABSTRACT
Multitarget agents simultaneously trigger molecules in functionally complementary pathways, and are therefore considered to have potential in effectively treating Alzheimer's disease (AD), which has a complex pathogenetic mechanism. In this study, the HDAC inhibitor core is incorporated into the acetylcholine esterase (ACE) inhibitor acridine-derived moiety and resulted in compounds that exhibited higher class IIa HDAC (4, 5, 7, and 9)- and class IIb HDAC6-inhibiting activity when compared to the pan-HDAC inhibitor SAHA in clinical practice. One of these compounds, 11b, displayed greater selectivity toward HDAC6 than other isoform enzymes. In contrast, the activity of compound 6a was selective toward class IIa HDAC and HDAC6. These two compounds exhibited strong activity against Aß-aggregation as well as significantly disrupted Aß-oligomer. Additionally, 11b and 6a strongly inhibited AChE. These experimental findings demonstrate that compounds 11b and 6a are HDAC-Aß-aggregation-AChE inhibitors. Notably, they can enhance neurite outgrowth, but with no significant neurotoxicity. Further biological evaluation revealed the various cellular effects of multitarget compounds 11b and 6a, which have the potential to treat AD.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Acridines
/
Histone Deacetylase Inhibitors
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Alzheimer Disease
/
Histone Deacetylases
Limits:
Animals
/
Humans
Language:
En
Journal:
Eur J Med Chem
Year:
2020
Document type:
Article
Affiliation country: