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N-Acylaminophenothiazines: Neuroprotective agents displaying multifunctional activities for a potential treatment of Alzheimer’s disease

2011; Elsevier BV; Volume: 46; Issue: 6 Linguagem: Inglês

10.1016/j.ejmech.2011.03.003

1768-3254

Gema C. González-Muñoz, Mariana P. Arce, Beatriz López‐Manzanares, Concepción Pérez, Alejandro Romero, Laura del Barrio, María Dolores Martin‐de‐Saavedra, Javier Egea, Rafael León, Mércedes Villarroya, Manuela G. López, Antonio G. Garcı́a, Santiago Conde, Marı́a Isabel Rodrı́guez-Franco,

Computational Drug Discovery Methods

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.