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

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

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.

• Jezik: Angleški jezik
• Ključne besede: cholinesterases, ferulic acid, molecular modelling, monoamine oxidase, radical-scavenger, antioxidant
• 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: 2022
• Št. strani: 18 str.
• Številčenje: Vol. 27, iss. 21, art. 7437
• PID: 20.500.12556/RUL-142354
• UDK: 616.894
• ISSN pri članku: 1420-3049
• DOI: 10.3390/molecules27217437
• COBISS.SI-ID: 127684867
• Datum objave v RUL: 02.11.2022

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.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: holinesteraze, ferulna kislina, molekularno modeliranje, monoaminooksidaza, lovilec radikalov, antioksidant

Projekti

• Financer: ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
• Številka projekta: P1-0208-2015
• Naslov: Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin