Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 13, Pages 9302-9320Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c00534
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Funding
- German Research Council (Deutsche Forschungsgemeinschaft) [DFG DE 1546/6-3]
- Campus France (PHC Procope)
- Federal Ministry of Education and Research (BmBF) [57387204]
- BayFrance (Franco-Bavarian University cooperation center) [FK03-2020]
- German Academic National Foundation (Studienstiftung des deutschen Volkes)
- International Doctoral Program Receptor Dynamics of the Elite Network of Bavaria (Elitenetzwerk Bayern)
- French Embassy
- German Academic Exchange Service (DAAD)
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A series of multitarget-directed ligands (MTDLs) were designed by functionalizing a pseudo-irreversible butyrylcholinesterase (BChE) inhibitor, showing retention of antioxidative properties in vitro and maintenance of hBChE inhibition in the submicromolar range. The most promising compound demonstrated high efficacy in a pharmacological Alzheimer's disease (AD) 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 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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