Selective Pseudo-irreversible Butyrylcholinesterase Inhibitors Transferring Antioxidant Moieties to the Enzyme Show Pronounced Neuroprotective Efficacy In Vitro and In Vivo in an Alzheimer's Disease Mouse Model

Matthias Scheiner; Matthias Hoffmann; Feng He; Eleonora Poeta; Arnaud Chatonnet; Barbara Monti; Tangui Maurice; Michael Decker

doi:10.1021/acs.jmedchem.1c00534

Selective Pseudo-irreversible Butyrylcholinesterase Inhibitors Transferring Antioxidant Moieties to the Enzyme Show Pronounced Neuroprotective Efficacy In Vitro and In Vivo in an Alzheimer's Disease Mouse Model

J Med Chem. 2021 Jul 8;64(13):9302-9320. doi: 10.1021/acs.jmedchem.1c00534. Epub 2021 Jun 21.

Authors

Matthias Scheiner¹, Matthias Hoffmann¹, Feng He¹, Eleonora Poeta², Arnaud Chatonnet³, Barbara Monti², Tangui Maurice⁴, Michael Decker¹

Affiliations

¹ Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, Julius Maximilian University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
² Department of Pharmacy and Biotechnology, University of Bologna, Via Selmi 3, 40126 Bologna, Italy.
³ DMEM, University of Montpellier, INRAE, 34060 Montpellier, France.
⁴ MMDN, University of Montpellier, INSERM, EPHE, 34095 Montpellier, France.

PMID: 34152756
DOI: 10.1021/acs.jmedchem.1c00534

Abstract

A series of multitarget-directed ligands (MTDLs) was designed by functionalizing a pseudo-irreversible butyrylcholinesterase (BChE) inhibitor. The obtained hybrids were investigated in vitro regarding their hBChE and hAChE inhibition, their enzyme kinetics, and their antioxidant physicochemical properties (DPPH, ORAC, metal chelating). In addition, in vitro assays were applied to investigate antioxidant effects using murine hippocampal HT22 cells and immunomodulatory effects on the murine microglial N9 cell line. The MTDLs retained their antioxidative properties compared to the parent antioxidant-moieties in vitro and the inhibition of hBChE was maintained in the submicromolar range. Representative compounds were tested in a pharmacological Alzheimer's disease (AD) mouse model and demonstrated very high efficacy at doses as low as 0.1 mg/kg. The most promising compound was also tested in BChE^-/- mice and showed reduced efficacy. In vivo neuroprotection by BChE inhibition can be effectively enhanced by incorporation of structurally diverse antioxidant moieties.

Publication types

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

MeSH terms

Acetylcholinesterase / metabolism
Alzheimer Disease / drug therapy*
Alzheimer Disease / metabolism
Animals
Antioxidants / chemical synthesis
Antioxidants / chemistry
Antioxidants / pharmacology*
Biphenyl Compounds / antagonists & inhibitors
Butyrylcholinesterase / deficiency
Butyrylcholinesterase / metabolism
Cell Survival / drug effects
Cells, Cultured
Cholinesterase Inhibitors / chemical synthesis
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / pharmacology*
Chromans / chemical synthesis
Chromans / chemistry
Chromans / pharmacology
Cinnamates / chemical synthesis
Cinnamates / chemistry
Cinnamates / pharmacology
Disease Models, Animal*
Dose-Response Relationship, Drug
Humans
Male
Melatonin / chemical synthesis
Melatonin / chemistry
Melatonin / pharmacology
Mice
Molecular Structure
Neuroprotective Agents / chemical synthesis
Neuroprotective Agents / chemistry
Neuroprotective Agents / pharmacology*
Picrates / antagonists & inhibitors
Structure-Activity Relationship

Substances

Antioxidants
Biphenyl Compounds
Cholinesterase Inhibitors
Chromans
Cinnamates
Neuroprotective Agents
Picrates
cinnamic acid
1,1-diphenyl-2-picrylhydrazyl
Acetylcholinesterase
Butyrylcholinesterase
Melatonin
6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid