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Novel arylcarbamate-N-acylhydrazones derivatives as promising BuChE inhibitors: Design, synthesis, molecular modeling and biological evaluation.
Novel arylcarbamate-N-acylhydrazones derivatives as promising BuChE inhibitors: Design, synthesis, molecular modeling and biological evaluation.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2021 Feb 15; Vol. 32, pp. 115991. Date of Electronic Publication: 2021 Jan 02. - Publication Year :
- 2021
-
Abstract
- A novel series of arylcarbamate-N-acylhydrazones derivatives have been designed and synthesized as potential anti-cholinesterase agents. In vitro studies revealed that these compounds demonstrated selective for butyrylcholinesterase (BuChE) with potent inhibitory activity. The compounds 10a-d, 12b and 12d were the most potent BuChE inhibitors with IC <subscript>50</subscript> values of 0.07-2.07 µM, highlighting the compound 10c (IC <subscript>50</subscript>  = 0.07 µM) which showed inhibitory activity 50 times greater than the reference drug donepezil (IC <subscript>50</subscript>  = 3.54 µM). The activity data indicates that the position of the carbamate group in the aromatic ring has a greater influence on the inhibitory activity of the derivatives. The enzyme kinetics studies indicate that the compound 10c has a non-competitive inhibition against BuChE with Ki value of 0.097 mM. Molecular modeling studies corroborated the in vitro inhibitory mode of interaction and show that compound 10c is stabilized into hBuChE by strong hydrogen bond interaction with Tyr128, π-π stacking interaction with Trp82 and CH⋯O interactions with His438, Gly121 and Glu197. Based on these data, compound10cwas identified as low-cost promising candidate for a drug prototype for AD treatment.<br /> (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Subjects :
- Acetylcholinesterase metabolism
Animals
Butyrylcholinesterase metabolism
Carbamates chemical synthesis
Carbamates chemistry
Cholinesterase Inhibitors chemical synthesis
Cholinesterase Inhibitors chemistry
Dose-Response Relationship, Drug
Electrophorus
Horses
Hydrazones chemical synthesis
Hydrazones chemistry
Models, Molecular
Molecular Structure
Structure-Activity Relationship
Carbamates pharmacology
Cholinesterase Inhibitors pharmacology
Drug Design
Hydrazones pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3391
- Volume :
- 32
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 33440318
- Full Text :
- https://doi.org/10.1016/j.bmc.2020.115991