Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 192, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2020.112193
Keywords
Histone deacetylase; Acetylcholine esterase; Acridine; Multitarget
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Funding
- Ministry of Science and Technology [MOST108-2320-B-038 -036, MOST108-2320-B-038-058-MY3]
- Taiwan Protein Project [MOST105-0210-01-12-01, MOST106-0210-01-15-04]
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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 acridineederived 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 A beta-aggregation as well as significantly disrupted Ab-oligomer. Additionally, 11b and 6a strongly inhibited AChE. These experimental findings demonstrate that compounds 11b and 6a are HDAC-A beta-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. (c) 2020 Elsevier Masson SAS. All rights reserved.
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