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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 Pèptids Agregació (Química) Alzheimer's disease Heterocyclic compounds Peptides 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. |
Note: | Reproducció del document publicat a: https://doi.org/10.3390/molecules25235773 |
It is part of: | Molecules, 2020, vol. 25(23), num. 5773 |
URI: | http://hdl.handle.net/2445/174316 |
Related resource: | https://doi.org/10.3390/molecules25235773 |
ISSN: | 1420-3049 |
Appears in Collections: | Articles publicats en revistes (Farmàcia, Tecnologia Farmacèutica i Fisicoquímica) |
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