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

European journal of medicinal chemistry (2011-03-23)
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
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.

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