N-hydroxy-N-propargylamide derivatives of ferulic acid : inhibitors of cholinesterases and monoamine oxidases

Bautista-Aguilera, Oscar M. (author), Alonso, José M. (author), Catto, Marco (author), Iriepa, Isabel (author), Knez, Damijan (author), Gobec, Stanislav (author), Marco-Contelles, José (author)

Alzheimer’s disease (AD) is a complex disorder characterized by impaired neurotransmission in cholinergic and monoaminergic neurons, which, in combination with the accumulation of misfolded proteins and increased oxidative stress, leads to the typical features of the disease at the biomolecular level. Given the limited therapeutic success of approved drugs, it is imperative to explore rationally supported therapeutic approaches to combat this disease. The search for novel scaffolds that bind to different receptors and inhibit AD disease-related enzymes could lead to new therapeutic solutions. Here, we describe N-hydroxy-N-propargylamide hybrids 1–6, which were designed by combining the structures of Contilisant—a multifunctional anti-AD ligand—and ferulic acid, a natural antioxidant with various other biological activities. Among the synthesized compounds, we identified compound 4 as a micromolar inhibitor of hAChE with a potent radical-scavenging capacity comparable to resveratrol and Trolox. In addition, compound 4 chelated copper(II) ions associated with amyloid β pathology, mitochondrial dysfunction, and oxidative stress. The promising in vitro activity combined with favorable drug-like properties and predicted blood‒brain barrier permeability make compound 4 a multifunctional ligand that merits further studies at the biochemical and cellular levels.

• Language: English
• Keywords: cholinesterases, ferulic acid, molecular modelling, monoamine oxidase, radical-scavenger, antioxidant
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2022
• Number of pages: 18 str.
• Numbering: Vol. 27, iss. 21, art. 7437
• PID: 20.500.12556/RUL-142354
• UDC: 616.894
• ISSN on article: 1420-3049
• DOI: 10.3390/molecules27217437
• COBISS.SI-ID: 127684867
• Publication date in RUL: 02.11.2022

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.

Secondary language

• Language: Slovenian
• Keywords: holinesteraze, ferulna kislina, molekularno modeliranje, monoaminooksidaza, lovilec radikalov, antioksidant

Projects

• Funder: ARRS - Slovenian Research Agency
• Project number: P1-0208-2015
• Name: Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin