Synthesis, molecular modelling and biological evaluation of novel heterodimeric, multiple ligands targeting cholinesterases and amyloid beta

Hebda, Michalina (avtor), Bajda, Marek (avtor), Więckowska, Anna (avtor), Szałaj, Natalia (avtor), Pasieka, Anna (avtor), Panek, Dawid (avtor), Godyń, Justyna (avtor), Wichur, Tomasz (avtor), Knez, Damijan (avtor), Gobec, Stanislav (avtor), Malawska, Barbara (avtor)

Cholinesterases and amyloid beta are one of the major biological targets in the search for a new and efficacious treatment of Alzheimer's disease. The study describes synthesis and pharmacological evaluation of new compounds designed as dual binding site acetylcholinesterase inhibitors. Among the synthesized compounds, two deserve special attention-compounds 42 and 13. The former is a saccharin derivative and the most potent and selective acetylcholinesterase inhibitor (EeAChE IC$_5$$_0$ = 70 nM). Isoindoline-1,3-dione derivative 13 displays balanced inhibitory potency against acetyl- and butyrylcholinesterase (BuChE) (EeAChE IC$_5$$_0$ = 0.76 µM, EqBuChE IC$_5$$_0$ = 0.618 µM), and it inhibits amyloid beta aggregation (35.8% at 10 µM). Kinetic studies show that the developed compounds act as mixed or non-competitive acetylcholinesterase inhibitors. According to molecular modelling studies, they are able to interact with both catalytic and peripheral active sites of the acetylcholinesterase. Their ability to cross the blood-brain barrier (BBB) was confirmed in vitro in the parallel artificial membrane permeability BBB assay. These compounds can be used as a solid starting point for further development of novel multifunctional ligands as potential anti-Alzheimer's agents.

• Jezik: Angleški jezik
• Ključne besede: cholinesterase inhibitors, molecular modelling, β-amyloid aggregation inhibitors, Alzheimer’s disease, multi-target-directed ligands (MTDL), PAMPA-BBB assay
• 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: 2016
• Št. strani: 24 str.
• Številčenje: Vol. 21, iss. 4, art. 410
• PID: 20.500.12556/RUL-130296
• UDK: 615.2:616.894
• ISSN pri članku: 1420-3049
• DOI: 10.3390/molecules21040410
• COBISS.SI-ID: 4051313
• Datum objave v RUL: 13.09.2021

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: 01.04.2016

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: tarčna zdravila, razvoj zdravil, zaviralci acetilholinesteraze, molekularno modeliranje, Alzheimerjeva bolezen