Melatonin- and Ferulic Acid-Based HDAC6 Selective Inhibitors Exhibit Pronounced Immunomodulatory Effects In Vitro and Neuroprotective Effects in a Pharmacological Alzheimer's Disease Mouse Model.

Abstract

The structures of melatonin and ferulic acid were merged into tertiary amide-based histone deacetylase 6 (HDAC6) inhibitors to develop multi-target-directed inhibitors for neurodegenerative diseases to incorporate antioxidant effects without losing affinity and selectivity at HDAC6. Structure-activity relationships led to compound 10b as a hybrid molecule showing pronounced and selective inhibition of HDAC6 (IC50 = 30.7 nM, > 25-fold selectivity over other subtypes). This compound shows comparable DPPH radical scavenging ability to ferulic acid, comparable ORAC value to melatonin and comparable Cu2+ chelating ability to EDTA. It also lacks neurotoxicity on HT-22 cells, exhibits a pronounced immunomodulatory effect, and is active in vivo showing significantly higher efficacy in an AD mouse model to prevent both Aβ25-35-induced spatial working and long-term memory dysfunction at lower dose (0.3 mg/kg) compared to positive control HDAC6 inhibitor ACY1215 and an equimolar mixture of the three entities ACY1215, melatonin and ferulic acid, suggesting potentially disease-modifying properties.

• Authors: Feng He, C James Chou, Matthias Scheiner, Eleonora Poeta, Natalia Yuan Chen, Sandra Gunesch, Matthias Hoffmann, Christoph Sotriffer, Barbara Monti, Tangui Maurice, Michael Decker
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 64 Issue 7 Pg. 3794-3812 (04 08 2021) ISSN: 1520-4804 [Electronic] United States
• PMID: 33769811 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Coumaric Acids
• Histone Deacetylase Inhibitors
• Immunologic Factors
• Neuroprotective Agents
• Tryptamines
• ferulic acid
• Hdac6 protein, mouse
• Histone Deacetylase 6
• Melatonin

Topics

• Alzheimer Disease (drug therapy, enzymology, metabolism)
• Animals
• Catalytic Domain
• Cell Line, Transformed
• Coumaric Acids (chemical synthesis, metabolism, therapeutic use)
• Histone Deacetylase 6 (antagonists & inhibitors, chemistry, metabolism)
• Histone Deacetylase Inhibitors (chemical synthesis, metabolism, therapeutic use)
• Immunologic Factors (chemical synthesis, metabolism, therapeutic use)
• Male
• Melatonin (analogs & derivatives, metabolism, therapeutic use)
• Mice
• Molecular Docking Simulation
• Neuroprotective Agents (chemical synthesis, metabolism, therapeutic use)
• Structure-Activity Relationship
• Tryptamines (chemical synthesis, metabolism, therapeutic use)