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.
Scheiner M., Hoffmann M., He F., Poeta E., Chatonnet A., Monti B., et al. (2021). 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. JOURNAL OF MEDICINAL CHEMISTRY, 64(13), 9302-9320 [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
Poeta E.Membro del Collaboration Group
;Monti B.Membro del Collaboration Group
;
2021
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
