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Title: In silico, NMR and pharmacological evaluation of an hydroxyoxindole cholinesterase inhibitor
Authors: Carreiro, Elisabete
Burke, Anthony
Bacalhau, Patricia
Martins, M. Rosário
Fernandes, Luis
Caldeira, A. Teresa
Candeias, Fátima
Guedes, Rita
Lopez, Óscar
Totobenazara, Jane
Issue Date: 15-Jan-2019
Publisher: Elsevier
Citation: Bioorganic & Medicinal Chemistry, 2019, 27(2), 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 μM 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 µmol.min−−1) than donepezil (0.112 µmol.min−−1) and the same level of inhibition for BuChE as donepezil (0.014 µmol.min−−1).
Type: article
Appears in Collections:CQE - Publicações - Artigos em Revistas Internacionais Com Arbitragem Científica

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