Structural isomerism and enhanced lipophilicity of pyrithione ligands of organoruthenium(II) complexes increase inhibition on AChE and BuChE
ID Kladnik, Jerneja (Author), ID Ristovski, Samuel (Author), ID Kljun, Jakob (Author), ID Defant, Andrea (Author), ID Mancini, Ines (Author), ID Sepčić, Kristina (Author), ID Turel, Iztok (Author)

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The increasing number of Alzheimer’s disease (AD) cases requires the development of new improved drug candidates, possessing the ability of more efficient treatment as well as less unwanted side effects. Cholinesterase enzymes are highly associated with the development of AD and thus represent important druggable targets. Therefore, we have synthesized eight organoruthenium(II) chlorido complexes 1a–h with pyrithione-type ligands (pyrithione = 1-hydroxypyridine-2(1H)-thione, a), bearing either pyrithione a, its methyl (b-e) or bicyclic aromatic analogues (f–h) and tested them for their inhibition towards electric eel acetylcholinesterase (eeAChE) and horse serum butyrylcholinesterase (hsBuChE). The experimental results have shown that the novel complex 1g with the ligand 1-hydroxyquinoline-2-(1H)-thione (g) improves the inhibition towards eeAChE (IC$_{50}$ = 4.9 µM) and even more potently towards hsBuChE (IC$_{50}$ = 0.2 µM) in comparison with the referenced 1a. Moreover, computational studies on Torpedo californica AChE have supported the experimental outcomes for 1g, possessing the lowest energy value among all tested complexes and have also predicted several interactions of 1g with the target protein. Consequently, we have shown that the aromatic ring extension of the ligand a, though only at the appropriate position, is a viable strategy to enhance the activity against cholinesterases.

Keywords:Alzheimer’s disease, acetylcholinesterase, butyrylcholinesterase, cholinesterase inhibitor, molecular docking, organoruthenium(II) complexes, pyrithione derivatives
Work type:Article
Typology:1.01 - Original Scientific Article
Organization:FKKT - Faculty of Chemistry and Chemical Technology
BF - Biotechnical Faculty
Publication status:Published
Publication version:Version of Record
Number of pages:17 str.
Numbering:Vol. 21, iss. 16, art. 5628
PID:20.500.12556/RUL-134383 This link opens in a new window
ISSN on article:1661-6596
DOI:10.3390/ijms21165628 This link opens in a new window
COBISS.SI-ID:24569091 This link opens in a new window
Publication date in RUL:12.01.2022
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Record is a part of a journal

Title:International journal of molecular sciences
Shortened title:Int. j. mol. sci.
Publisher:Molecular Diversity Preservation International MDPI
COBISS.SI-ID:36217605 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:06.08.2020

Secondary language

Keywords:rutenij, organorutenijevi kompleksi, ligandi, derivati piritiona, Alzheimerjeva bolezen


Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Project number:P1-0175
Name:Napredna anorganska kemija

Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Project number:P1-0207
Name:Toksini in biomembrane

Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Funding programme:Young researchers

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