Jerneja Kladnik (Author), Samuel Ristovski (Author), Jakob Kljun (Author), Andrea Defant (Author), Ines Mancini (Author), Kristina Sepčić (Author), Iztok Turel (Author)

Abstract

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

rutenij;organorutenijevi kompleksi;ligandi;derivati piritiona;Alzheimerjeva bolezen;

Data

Language: English
Year of publishing:
Typology: 1.01 - Original Scientific Article
Organization: UL FKKT - Faculty of Chemistry and Chemical Technology
UDC: 546.96
COBISS: 24569091 Link will open in a new window
ISSN: 1661-6596
Views: 275
Downloads: 84
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Other data

Secondary language: Slovenian
Secondary keywords: rutenij;organorutenijevi kompleksi;ligandi;derivati piritiona;Alzheimerjeva bolezen;
Type (COBISS): Article
Pages: str. 1-17
Volume: ǂVol. ǂ21
Issue: ǂiss. ǂ16
Chronology: Aug. 2020
DOI: 10.3390/ijms21165628
ID: 14259058