丁酰胆碱酯酶
化学
神经保护
体内
体外
抗氧化剂
药理学
乙酰胆碱酯酶
酶抑制剂
胆碱酯酶
阿尔茨海默病
退行性疾病
阿切
生物化学
酶
疾病
神经科学
中枢神经系统疾病
内科学
医学
生物技术
生物
作者
Matthias Scheiner,Matthias Hoffmann,Feng He,Eleonora Poeta,Arnaud Chatonnet,Barbara Monti,Tangui Maurice,Michael Decker
标识
DOI:10.1021/acs.jmedchem.1c00534
摘要
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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