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Title: Pharmacophore Modeling and 3D-QSAR Study of Indole and Isatin Derivatives as Antiamyloidogenic Agents Targeting Alzheimer's Disease
Author: Purgatorio, Rosario
Gambacorta, Nicola
Catto, Marco
de Candia, Modesto
Pisani, Leonardo
Espargaró Colomé, Alba
Sabaté Lagunas, Raimon
Cellamare, Saverio
Nicolotti, Orazio
Altomare, Cosimo D.
Keywords: Malaltia d'Alzheimer
Compostos heterocíclics
Agregació (Química)
Alzheimer's disease
Heterocyclic compounds
Aggregation (Chemistry)
Issue Date: 7-Dec-2020
Publisher: MDPI
Abstract: Thirty-six novel indole-containing compounds, mainly 3-(2-phenylhydrazono) isatins and structurally related 1H-indole-3-carbaldehyde derivatives, were synthesized and assayed as inhibitors of beta amyloid (Aβ) aggregation, a hallmark of pathophysiology of Alzheimer's disease. The newly synthesized molecules spanned their IC50 values from sub- to two-digit micromolar range, bearing further information into structure-activity relationships. Some of the new compounds showed interesting multitarget activity, by inhibiting monoamine oxidases A and B. A cell-based assay in tau overexpressing bacterial cells disclosed a promising additional activity of some derivatives against tau aggregation. The accumulated data of either about ninety published and thirty-six newly synthesized molecules were used to generate a pharmacophore hypothesis of antiamyloidogenic activity exerted in a wide range of potencies, satisfactorily discriminating the 'active' compounds from the 'inactive' (poorly active) ones. An atom-based 3D-QSAR model was also derived for about 80% of 'active' compounds, i.e., those achieving finite IC50 values lower than 100 μM. The 3D-QSAR model (encompassing 4 PLS factors), featuring acceptable predictive statistics either in the training set (n = 45, q2 = 0.596) and in the external test set (n = 14, r2ext = 0.695), usefully complemented the pharmacophore model by identifying the physicochemical features mainly correlated with the Aβ anti-aggregating potency of the indole and isatin derivatives studied herein.
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It is part of: Molecules, 2020, vol. 25(23), num. 5773
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ISSN: 1420-3049
Appears in Collections:Articles publicats en revistes (Farmàcia, Tecnologia Farmacèutica i Fisicoquímica)

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