Pharmacophore Modeling and 3D-QSAR Study of Indole and Isatin Derivatives as Antiamyloidogenic Agents Targeting Alzheimer's Disease

• Published in: Molecules (Basel, Switzerland) Switzerland), 2020-12, Vol.25 (23), p.5773
• Main Authors: Purgatorio, Rosa, Gambacorta, Nicola, Catto, Marco, de Candia, Modesto, Pisani, Leonardo, Espargaró, Alba, Sabaté, Raimon, Cellamare, Saverio, Nicolotti, Orazio, Altomare, Cosimo D
• Format: Article
• Language: English
• Subjects: 3D-QSAR; Alzheimer Disease - drug therapy; Alzheimer's disease; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - metabolism; antiamyloid agents; Chemistry Techniques, Synthetic; Cytoprotection - drug effects; Drug Design; Humans; indole derivatives; Indoles; Indoles - chemistry; Indoles - pharmacology; Isatin - chemistry; Isatin - pharmacology; isatin hydrazones; Ligands; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Structure; multitarget-directed ligands; Peptide Fragments - antagonists & inhibitors; Peptide Fragments - chemistry; Peptide Fragments - metabolism; Pharmacology; Protein Aggregates - drug effects; Proteins; Quantitative Structure-Activity Relationship; Structure-activity relationships; Tau protein; β-Amyloid
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules25235773

Thirty-six novel indole-containing compounds, mainly 3-(2-phenylhydrazono) isatins and structurally related 1 -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 IC 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 IC values lower than 100 μM. The 3D-QSAR model (encompassing 4 PLS factors), featuring acceptable predictive statistics either in the training set ( = 45, q = 0.596) and in the external test set ( = 14, r = 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.