Novel pyridazinone derivatives as butyrylcholinesterase inhibitors.

Autor: Dundar Y; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Ankara, Turkey. Electronic address: yasemina@gazi.edu.tr., Kuyrukcu O; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Ankara, Turkey., Eren G; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Ankara, Turkey., Senol Deniz FS; Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, 06330 Ankara, Turkey., Onkol T; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Ankara, Turkey., Orhan IE; Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, 06330 Ankara, Turkey.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2019 Nov; Vol. 92, pp. 103304. Date of Electronic Publication: 2019 Sep 18.
DOI: 10.1016/j.bioorg.2019.103304
Abstrakt: In the current study, forty-four new [3-(2/3/4-methoxyphenyl)-6-oxopyridazin-1(6H)-yl]methyl carbamate derivatives were synthesized and evaluated for their ability to inhibit electric eel acetylcholinesterase (EeAChE) and equine butyrylcholinesterase (eqBuChE) enzymes. According to the inhibitory activity results, [3-(2-methoxyphenyl)-6-oxopyridazin-1(6H)-yl]methyl heptylcarbamate (16c, eqBuChE, IC 50  = 12.8 μM; EeAChE, no inhibition at 100 μM) was the most potent eqBuChE inhibitor among the synthesized compounds and was found to be a moderate inhibitor compared to donepezil (eqBuChE, IC 50  = 3.25 μM; EeAChE, IC 50  = 0.11 μM). Kinetic and molecular docking studies indicated that compounds 16c and 14c (hexylcarbamate derivative, eqBuChE, IC 50  = 35 μM; EeAChE, no inhibition at 100 μM) were mixed-type inhibitors which accommodated within the catalytic active site (CAS) and peripheral anionic site (PAS) of hBuChE through stable hydrogen bonding and π-π stacking. Furthermore, it was determined that [3-(2-methoxyphenyl)-6-oxopyridazin-1(6H)-yl]methyl (4-methylphenyl)carbamate 7c (eqBuChE, IC 50  = 34.5 μM; EeAChE, 38.9% inhibition at 100 μM) was the most active derivative against EeAChE and a competitive inhibitor binding to the CAS of hBuChE. As a result, 6-(2-methoxyphenyl)pyridazin-3(2H)-one scaffold is important for the inhibitory activity and compounds 7c, 14c and 16c might be considered as promising lead candidates for the design and development of selective BuChE inhibitors for Alzheimer's disease treatment.
(Copyright © 2019 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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