title: 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.affiliation: Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain.
authors.forename: Gema C
authors.initials: GC
authors.lastname: González-Muñoz
authors.forename: Mariana P
authors.initials: MP
authors.lastname: Arce
authors.forename: Beatriz
authors.initials: B
authors.lastname: López
authors.forename: Concepción
authors.initials: C
authors.lastname: Pérez
authors.forename: Alejandro
authors.initials: A
authors.lastname: Romero
authors.forename: Laura
authors.initials: L
authors.lastname: del Barrio
authors.forename: María Dolores
authors.initials: MD
authors.lastname: Martín-de-Saavedra
authors.forename: Javier
authors.initials: J
authors.lastname: Egea
authors.forename: Rafael
authors.initials: R
authors.lastname: León
authors.forename: Mercedes
authors.initials: M
authors.lastname: Villarroya
authors.forename: Manuela G
authors.initials: MG
authors.lastname: López
authors.forename: Antonio G
authors.initials: AG
authors.lastname: García
authors.forename: Santiago
authors.initials: S
authors.lastname: Conde
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Rodríguez-Franco
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000633:toxicity; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002091:Butyrylcholinesterase / Q000378:metabolism; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D019319:Okadaic Acid / Q000037:antagonists & inhibitors / Q000633:toxicity; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000633:toxicity; D010640:Phenothiazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D016229:Amyloid beta-Peptides; D000970:Antineoplastic Agents; D002800:Cholinesterase Inhibitors; D010446:Peptide Fragments; D010640:Phenothiazines; C075222:amyloid beta-protein (1-42); D019319:Okadaic Acid; D002091:Butyrylcholinesterase; D002118:Calcium