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

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

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.

• Language: English
• Keywords: cholinesterase inhibitors, molecular modelling, β-amyloid aggregation inhibitors, Alzheimer’s disease, multi-target-directed ligands (MTDL), PAMPA-BBB assay
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2016
• Number of pages: 24 str.
• Numbering: Vol. 21, iss. 4, art. 410
• PID: 20.500.12556/RUL-130296
• UDC: 615.2:616.894
• ISSN on article: 1420-3049
• DOI: 10.3390/molecules21040410
• COBISS.SI-ID: 4051313
• Publication date in RUL: 13.09.2021

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.
• Licensing start date: 01.04.2016

Secondary language

• Language: Slovenian
• Keywords: tarčna zdravila, razvoj zdravil, zaviralci acetilholinesteraze, molekularno modeliranje, Alzheimerjeva bolezen