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

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

doi:10.1016/j.ejmech.2011.03.003

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

Eur J Med Chem. 2011 Jun;46(6):2224-35. doi: 10.1016/j.ejmech.2011.03.003. Epub 2011 Mar 21.

Authors

Gema C González-Muñoz¹, 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

Affiliation

¹ Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain.

PMID: 21420206
DOI: 10.1016/j.ejmech.2011.03.003

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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