Synthesis, molecular modelling and biological evaluation of novel heterodimeric, multiple ligands targeting cholinesterases and amyloid beta
ID Hebda, Michalina (Author), ID Bajda, Marek (Author), ID Więckowska, Anna (Author), ID Szałaj, Natalia (Author), ID Pasieka, Anna (Author), ID Panek, Dawid (Author), ID Godyń, Justyna (Author), ID Wichur, Tomasz (Author), ID Knez, Damijan (Author), ID Gobec, Stanislav (Author), ID Malawska, Barbara (Author)

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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.

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
Number of pages:24 str.
Numbering:Vol. 21, iss. 4, art. 410
PID:20.500.12556/RUL-130296 This link opens in a new window
ISSN on article:1420-3049
DOI:10.3390/molecules21040410 This link opens in a new window
COBISS.SI-ID:4051313 This link opens in a new window
Publication date in RUL:13.09.2021
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Shortened title:Molecules
COBISS.SI-ID:18462981 This link opens in a new window


License:CC BY 4.0, Creative Commons Attribution 4.0 International
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

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


Funder:Drugi - Drug financer ali več financerjev
Funding programme:Polish Ministry for Science and High Education
Project number:N N405 163339

Funder:Drugi - Drug financer ali več financerjev
Funding programme:National Science Center of Poland
Project number:2012/07/B/NZ7/04253

Funder:Drugi - Drug financer ali več financerjev
Funding programme:Jagiellonian University Collegium Medicum
Project number:K/Z S/004657

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