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 (IC50 = 4.9 μM) and even more potently towards hsBuChE (IC50 = 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.
Highlights
Due to world’s aging population there is a progressive increase of the cases related to dementia [1]
The structure was modified as follows: the ligand and all of the crystallization water molecules were removed, with the file saved in pdb extension; all hydrogen atoms were added using AutoDock Tools (ADT), and the Gasteigere Marsili charges were calculated, with the resulting file saved in pdbqt extension; rotatable bonds were defined for each ligand molecule
For the best two performing complexes, 1e and 1g against eel acetylcholinesterase (eeAChE) and horse serum butyrylcholinesterase (hsBuChE), NMR stability tests in different D2O solutions were performed and showed that complexes remained stable
Summary
Due to world’s aging population there is a progressive increase of the cases related to dementia [1]. Complex 1a showed no cytotoxicity against non-cancer HUVEC and NHEK-1 cells and did not express any unwanted physiological response on the neuromuscular transition at pharmaceutically relevant concentrations The latter finding is of the particular importance, as many AChE inhibitors show many adverse effects, including uncontrolled muscle contraction and the failure of neuromuscular transmission in the peripheric nervous system [23]. We have shown by 1H NMR that compound 1a is stable in DMSO-d6/D2O solvent system [22] and later confirmed the stability of 1a complex in the D2O solution containing NaCl [24]. Similar analyses changing solvent and time displayed only [M − Cl]+ ion with clusters at m/z 376 for the isomeric compounds 1c–e, at m/z 362 for 1a and at m/z 412 for 1f–h
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