N-acylaminophenothiazines: neuroprotective agents displaying multifunctional activities for a potential treatment of Alzheimer's disease.

Abstract

We have previously reported the multifunctional profile of N-(3-chloro-10H-phenothiazin-10-yl)-3-(dimethylamino)propanamide (1) as an effective neuroprotectant and selective butyrylcholinesterase inhibitor. In this paper, we have developed a series of N-acylaminophenothiazines obtained from our compound library or newly synthesised. At micro- and sub-micromolar concentrations, these compounds selectively inhibited butyrylcholinesterase (BuChE), protected neurons against damage caused by both exogenous and mitochondrial free radicals, showed low toxicity, and could penetrate into the CNS. In addition, N-(3-chloro-10H-phenothiazin-10-yl)-2-(pyrrolidin-1-yl)acetamide (11) modulated the cytosolic calcium concentration and protected human neuroblastoma cells against several toxics, such as calcium overload induced by an L-type Ca2+-channel agonist, tau-hyperphosphorylation induced by okadaic acid and Aβ peptide.

• Authors: Gema C González-Muñoz, Mariana P Arce, Beatriz López, Concepción Pérez, Alejandro Romero, Laura del Barrio, María Dolores Martín-de-Saavedra, Javier Egea, Rafael León, Mercedes Villarroya, Manuela G López, Antonio G García, Santiago Conde, María Isabel Rodríguez-Franco
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 46 Issue 6 Pg. 2224-35 (Jun 2011) ISSN: 1768-3254 [Electronic] France
• PMID: 21420206 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Chemical References

• Amyloid beta-Peptides
• Antineoplastic Agents
• Cholinesterase Inhibitors
• Peptide Fragments
• Phenothiazines
• amyloid beta-protein (1-42)
• Okadaic Acid
• Butyrylcholinesterase
• Calcium

Topics

• Alzheimer Disease (drug therapy, enzymology)
• Amyloid beta-Peptides (antagonists & inhibitors, toxicity)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Butyrylcholinesterase (metabolism)
• Calcium (antagonists & inhibitors, metabolism)
• Cell Death (drug effects)
• Cell Survival (drug effects)
• Cholinesterase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Humans
• Molecular Structure
• Okadaic Acid (antagonists & inhibitors, toxicity)
• Peptide Fragments (antagonists & inhibitors, toxicity)
• Phenothiazines (chemical synthesis, chemistry, pharmacology)
• Stereoisomerism
• Structure-Activity Relationship
• Tumor Cells, Cultured