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

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 prop...

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Published inJournal of medicinal chemistry Vol. 64; no. 13; pp. 9302 - 9320
Main Authors Scheiner, Matthias, Hoffmann, Matthias, He, Feng, Poeta, Eleonora, Chatonnet, Arnaud, Monti, Barbara, Maurice, Tangui, Decker, Michael
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 08.07.2021
Amer Chemical Soc
Subjects
Chemistry, Medicinal
Life Sciences
Life Sciences & Biomedicine
Pharmaceutical sciences
Pharmacology
Pharmacology & Pharmacy
Science & Technology
DONEPEZIL
CAPACITY
TARGET-DIRECTED LIGANDS
OXIDATIVE STRESS
ACETYLCHOLINESTERASE
MELATONIN
TROLOX HYBRIDS
TOXICITY
CHOLINESTERASE-INHIBITORS
PEPTIDE
SOXIDATIVE STRESS
TARGET-DIRECTED LIGAND
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Summary: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.
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ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.1c00534