4-Aryl-4-oxo-N-phenyl-2-aminylbutyramides as acetyl- and butyrylcholinesterase inhibitors. Preparation, anticholinesterase activity, docking study, and 3D structure-activity relationship based on molecular interaction fields
Apstrakt
Synthesis and anticholinesterase activity of 4-aryl-4-oxo-N-phenyl-2-aminylbutyramides, novel class of reversible, moderately potent cholinesterase inhibitors, are reported. Simple substituent variation on aroyl moiety changes anti-AChE activity for two orders of magnitude; also substitution and type of hetero(ali)cycle in position 2 of butanoic moiety govern AChE/BChE selectivity. The most potent compounds showed mixed-type inhibition, indicating their binding to free enzyme and enzyme-substrate complex. Alignment-independent 3D QSAR study on reported compounds, and compounds having similar potencies obtained from the literature, confirmed that alkyl substitution on aroyl moiety of molecules is requisite for inhibition activity. The presence of hydrophobic moiety at close distance from hydrogen bond acceptor has favorable influence on inhibition potency. Docking studies show that compounds probably bind in the middle of the AChE active site gorge, but are buried deeper inside BChE act...ive site gorge, as a consequence of larger BChE gorge void. (C) 2009 Elsevier Ltd. All rights reserved.
Ključne reči:
4-Aryl-4-oxo-N-phenyl-2-aminylbutyramides / Anticholinesterase activity / Mixed-type reversible inhibitors / Alignment-independent 3D QSAR / Docking studyIzvor:
Bioorganic and Medicinal Chemistry, 2010, 18, 3, 1181-1193Izdavač:
- Pergamon-Elsevier Science Ltd, Oxford
DOI: 10.1016/j.bmc.2009.12.042
ISSN: 0968-0896
PubMed: 20061157
WoS: 000274153600023
Scopus: 2-s2.0-75349114471
Kolekcije
Institucija/grupa
Hemijski fakultet / Faculty of ChemistryTY - JOUR AU - Vitorović-Todorović, Maja D. AU - Juranić, Ivan O. AU - Mandić, Ljuba M. AU - Drakulić, Branko J. PY - 2010 UR - https://cherry.chem.bg.ac.rs/handle/123456789/875 AB - Synthesis and anticholinesterase activity of 4-aryl-4-oxo-N-phenyl-2-aminylbutyramides, novel class of reversible, moderately potent cholinesterase inhibitors, are reported. Simple substituent variation on aroyl moiety changes anti-AChE activity for two orders of magnitude; also substitution and type of hetero(ali)cycle in position 2 of butanoic moiety govern AChE/BChE selectivity. The most potent compounds showed mixed-type inhibition, indicating their binding to free enzyme and enzyme-substrate complex. Alignment-independent 3D QSAR study on reported compounds, and compounds having similar potencies obtained from the literature, confirmed that alkyl substitution on aroyl moiety of molecules is requisite for inhibition activity. The presence of hydrophobic moiety at close distance from hydrogen bond acceptor has favorable influence on inhibition potency. Docking studies show that compounds probably bind in the middle of the AChE active site gorge, but are buried deeper inside BChE active site gorge, as a consequence of larger BChE gorge void. (C) 2009 Elsevier Ltd. All rights reserved. PB - Pergamon-Elsevier Science Ltd, Oxford T2 - Bioorganic and Medicinal Chemistry T1 - 4-Aryl-4-oxo-N-phenyl-2-aminylbutyramides as acetyl- and butyrylcholinesterase inhibitors. Preparation, anticholinesterase activity, docking study, and 3D structure-activity relationship based on molecular interaction fields VL - 18 IS - 3 SP - 1181 EP - 1193 DO - 10.1016/j.bmc.2009.12.042 ER -
@article{ author = "Vitorović-Todorović, Maja D. and Juranić, Ivan O. and Mandić, Ljuba M. and Drakulić, Branko J.", year = "2010", abstract = "Synthesis and anticholinesterase activity of 4-aryl-4-oxo-N-phenyl-2-aminylbutyramides, novel class of reversible, moderately potent cholinesterase inhibitors, are reported. Simple substituent variation on aroyl moiety changes anti-AChE activity for two orders of magnitude; also substitution and type of hetero(ali)cycle in position 2 of butanoic moiety govern AChE/BChE selectivity. The most potent compounds showed mixed-type inhibition, indicating their binding to free enzyme and enzyme-substrate complex. Alignment-independent 3D QSAR study on reported compounds, and compounds having similar potencies obtained from the literature, confirmed that alkyl substitution on aroyl moiety of molecules is requisite for inhibition activity. The presence of hydrophobic moiety at close distance from hydrogen bond acceptor has favorable influence on inhibition potency. Docking studies show that compounds probably bind in the middle of the AChE active site gorge, but are buried deeper inside BChE active site gorge, as a consequence of larger BChE gorge void. (C) 2009 Elsevier Ltd. All rights reserved.", publisher = "Pergamon-Elsevier Science Ltd, Oxford", journal = "Bioorganic and Medicinal Chemistry", title = "4-Aryl-4-oxo-N-phenyl-2-aminylbutyramides as acetyl- and butyrylcholinesterase inhibitors. Preparation, anticholinesterase activity, docking study, and 3D structure-activity relationship based on molecular interaction fields", volume = "18", number = "3", pages = "1181-1193", doi = "10.1016/j.bmc.2009.12.042" }
Vitorović-Todorović, M. D., Juranić, I. O., Mandić, L. M.,& Drakulić, B. J.. (2010). 4-Aryl-4-oxo-N-phenyl-2-aminylbutyramides as acetyl- and butyrylcholinesterase inhibitors. Preparation, anticholinesterase activity, docking study, and 3D structure-activity relationship based on molecular interaction fields. in Bioorganic and Medicinal Chemistry Pergamon-Elsevier Science Ltd, Oxford., 18(3), 1181-1193. https://doi.org/10.1016/j.bmc.2009.12.042
Vitorović-Todorović MD, Juranić IO, Mandić LM, Drakulić BJ. 4-Aryl-4-oxo-N-phenyl-2-aminylbutyramides as acetyl- and butyrylcholinesterase inhibitors. Preparation, anticholinesterase activity, docking study, and 3D structure-activity relationship based on molecular interaction fields. in Bioorganic and Medicinal Chemistry. 2010;18(3):1181-1193. doi:10.1016/j.bmc.2009.12.042 .
Vitorović-Todorović, Maja D., Juranić, Ivan O., Mandić, Ljuba M., Drakulić, Branko J., "4-Aryl-4-oxo-N-phenyl-2-aminylbutyramides as acetyl- and butyrylcholinesterase inhibitors. Preparation, anticholinesterase activity, docking study, and 3D structure-activity relationship based on molecular interaction fields" in Bioorganic and Medicinal Chemistry, 18, no. 3 (2010):1181-1193, https://doi.org/10.1016/j.bmc.2009.12.042 . .