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|Title: ||Pharmacological evaluation and SAR studies of oxindole derivatives as cholinesterase inhibitors|
|Authors: ||BURKE, Anthony|
|Editors: ||Waldmann, Herbert|
|Keywords: ||Alzheimer's disease|
|Issue Date: ||15-Jan-2019|
|Citation: ||Pharmacological evaluation and SAR studies of oxindole derivatives as cholinesterase inhibitors, Patrícia Bacalhau, Luís Fernandes, Fátima Candeias, Elisabete Carreiro, Óscar López, Rita Guedes, Teresa Caldeira, Rosário Martins, Anthony J. Burke, Bioorganic and Medicinal Chemistry, 2019, 27, 354-363.|
|Abstract: ||From a screening study of various potential inhibitors for cholinesterases (ChEs), compound (rac)-1(4-((3-hydroxy-2-oxo-3-phenylindolin-1-yl)methyl) piperidin-1-ium chloride) showed an IC50 of 18 mu M for butyrylcholinesterase (BuChE). Herein we present a toxicological and pharmacological evaluation of (rac)-1 to determine its potential for use as an alternative ChE inhibitor for the treatment of Alzheimer's disease. The strategy adopted included in vivo and ex vivo studies with mouse models, Molecular Modelling and Saturation Transfer Difference (STD) NMR studies.
Preliminary molecular docking studies were conducted with both (R) and (S)-1 with acetylcholinesterase (AChE) and BuChE, prior to advancing to the mouse model, and indeed favorable interactions were observed, with (R)-1 showing the best binding with AChE and (S)-1 with BuChE. STD-NMR studies were used to successfully validate these results. Toxicological studies were also conducted using the Artemia salina model, with donepezil as reference. It was found that in the in vivo mouse studies that (rac)-1 presented a slightly better inhibition of AChE (0.096 mu mol.min(-1).mg(-1)) than donepezil (0.112 mu mol.min(-1).mg(-1)) and the same level of inhibition for BuChE as donepezil (0.014 mu mol.min(-1).mg(-1)).|
|Appears in Collections:||CQE - Publicações - Artigos em Revistas Internacionais Com Arbitragem Científica|
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