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

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

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.

• Jezik: Angleški jezik
• Ključne besede: Alzheimer's disease, butyrylcholinesterase, monoamine oxidase B, inhibitors, multi-target-directed ligands, multifunctional ligands
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2021
• Št. strani: 17 str.
• Številčenje: Vol. 26, iss. 14, art. 4118
• PID: 20.500.12556/RUL-135594
• UDK: 615.4:54:616.894
• ISSN pri članku: 1420-3049
• DOI: 10.3390/molecules26144118
• COBISS.SI-ID: 69610499
• Datum objave v RUL: 21.03.2022

Gradivo je del revije

• Naslov: Molecules
• Skrajšan naslov: Molecules
• Založnik: MDPI
• ISSN: 1420-3049
• COBISS.SI-ID: 18462981

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.
• Začetek licenciranja: 06.07.2021

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: butirilholinesteraze, zaviralci, monoamin oksidaza B, večfunkcijski ligandi, tarčni ligandi, Alzheimerjeva bolezen, farmacevtska kemija