4-phenethyl-1-propargylpiperidine-derived dual inhibitors of butyrylcholinesterase and monoamine oxidase B

Mazej, Tjaša (author), Knez, Damijan (author), Meden, Anže (author), Gobec, Stanislav (author), Sova, Matej (author)

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 (IC$_{50}$ of 4.3 µM) and hBChE (IC$_{50}$ 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.

• Language: English
• Keywords: Alzheimer's disease, butyrylcholinesterase, monoamine oxidase B, inhibitors, multi-target-directed ligands, multifunctional ligands
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2021
• Number of pages: 17 str.
• Numbering: Vol. 26, iss. 14, art. 4118
• PID: 20.500.12556/RUL-135594
• UDC: 615.4:54:616.894
• ISSN on article: 1420-3049
• DOI: 10.3390/molecules26144118
• COBISS.SI-ID: 69610499
• Publication date in RUL: 21.03.2022

Record is a part of a journal

• Title: Molecules
• Shortened title: Molecules
• Publisher: MDPI
• ISSN: 1420-3049
• COBISS.SI-ID: 18462981

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
• Licensing start date: 06.07.2021

Secondary language

• Language: Slovenian
• Keywords: butirilholinesteraze, zaviralci, monoamin oksidaza B, večfunkcijski ligandi, tarčni ligandi, Alzheimerjeva bolezen, farmacevtska kemija