4-Phenethyl-1-Propargylpiperidine-Derived Dual Inhibitors of Butyrylcholinesterase and Monoamine Oxidase B

Molecules

Stanislav Gobec¹  Anže Meden¹  Tjaša Mazej¹  Damijan Knez¹  Matej Sova¹ 

[1] Faculty of Pharmacy, University of Ljubljana, Aškerčeva Cesta 7, SI-1000 Ljubljana, Slovenia;

关键词: Alzheimer’s disease;    butyrylcholinesterase;    monoamine oxidase B;    inhibitors;    multi-target-directed ligands;    multifunctional ligands;   

DOI  :  10.3390/molecules26144118

来源: DOAJ

【 摘 要 】

The multi-target-directed ligands (MTDLs) strategy is encouraged for the development of novel modulators targeting multiple pathways in the neurodegenerative cascade typical for Alzheimer’s disease (AD). Based on the structure of an in-house irreversible monoamine oxidase B (MAO-B) inhibitor, we aimed to introduce a carbamate moiety on the aromatic ring to impart cholinesterase (ChE) inhibition, and to furnish multifunctional ligands targeting two enzymes that are intricately involved in AD pathobiology. In this study, we synthesized three dual hMAO-B/hBChE inhibitors 13–15, with compound 15 exhibiting balanced, low micromolar inhibition of hMAO-B (IC₅₀ of 4.3 µM) and hBChE (IC₅₀ of 8.5 µM). The docking studies and time-dependent inhibition of hBChE confirmed the initial expectation that the introduced carbamate moiety is responsible for covalent inhibition. Therefore, dual-acting compound 15 represents an excellent starting point for further optimization of balanced MTDLs

【 授权许可】

Unknown