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

Abstract

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 [micro]M) and hBChE (IC50 of 8.5 [micro]M). 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.

Keywords

Alzheimer's disease;butyrylcholinesterase;monoamine oxidase B;inhibitors;multi-target-directed ligands;multifunctional ligands;

Data

Language: English
Year of publishing:
Typology: 1.01 - Original Scientific Article
Organization: UL FFA - Faculty of Pharmacy
UDC: 615.4:54:616.894
COBISS: 69610499 Link will open in a new window
ISSN: 1420-3049
Views: 150
Downloads: 62
Average score: 0 (0 votes)
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Other data

Secondary language: Slovenian
Secondary keywords: butirilholinesteraze;zaviralci;monoamin oksidaza B;večfunkcijski ligandi;tarčni ligandi;Alzheimerjeva bolezen;Farmacevtska kemija;
Type (COBISS): Article
Pages: str. 1-17
Volume: ǂVol. ǂ26
Issue: ǂiss. ǂ14
Chronology: 2021
DOI: 10.3390/molecules26144118
ID: 14808630