Novel pyridazinone derivatives as butyrylcholinesterase inhibitors |
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Affiliation: | 2. St. Vincent Indianapolis Hospital, Indianapolis, IN, United States;1. Laboratory of Applied Chemistry and Environment (LCAE), Department of Chemistry, Faculty of Sciences, Mohammed I University, Oujda, Morocco;2. Laboratory of Analytical Chemistry and Bromatology, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco;3. Department of Physics, Faculty of Arts and Sciences, OndokuzMayıs University, 55139 Samsun, Turkey;4. Institute of Nursing Professions and Health Techniques Fez, EL Ghassani Hospital, Fez30000, Morocco;5. Cátedra de Química General, Instituto de QuímicaInorgánica, Facultad de Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán, Ayacucho 471, 4000 Tucumán, Argentina |
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Abstract: | 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, IC50 = 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, IC50 = 3.25 μM; EeAChE, IC50 = 0.11 μM). Kinetic and molecular docking studies indicated that compounds 16c and 14c (hexylcarbamate derivative, eqBuChE, IC50 = 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, IC50 = 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. |
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Keywords: | Alzheimer’s disease Pyridazinone derivatives Acetylcholinesterase inhibitors Butyrylcholinesterase inhibitors Docking |
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