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

Feng He; C James Chou; Matthias Scheiner; Eleonora Poeta; Natalia Yuan Chen; Sandra Gunesch; Matthias Hoffmann; Christoph Sotriffer; Barbara Monti; Tangui Maurice; Michael Decker

doi:10.1021/acs.jmedchem.0c01940

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

J Med Chem. 2021 Apr 8;64(7):3794-3812. doi: 10.1021/acs.jmedchem.0c01940. Epub 2021 Mar 26.

Affiliations

¹ Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, Julius Maximilian University of Würzburg, Am Hubland, Würzburg 97074, Germany.
² Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, Medical University of South Carolina, Charleston, South Carolina 29425, United States.
³ Department of Pharmacy and Biotechnologies, University of Bologna, Via Selmi 3, Bologna 40126, Italy.
⁴ MMDN, Univ Montpellier, EPHE, INSERM, Montpellier 34095, France.

PMID: 33769811
DOI: 10.1021/acs.jmedchem.0c01940

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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