Old phenothiazine and dibenzothiadiazepine derivatives for tomorrow's neuroprotective therapies against neurodegenerative diseases.

摘要

From an in-house library of compounds, five phenothiazines and one dibenzothiadiazepine were selected to be tested in neuroprotective and cholinergic assays. Three of them, derived from the N-alkylphenothiazine, the N-acylaminophenothiazine, and the 1,4,5-dibenzo[b,f]thiadiazepine system, protected human neuroblastoma cells against oxidative stress generated by both exogenous and mitochondrial free radicals. They could also penetrate the CNS, according to an in vitro blood-brain barrier model, and an N-acylaminophenothiazine derivative behaved as a selective inhibitor of butyrylcholinesterase. Free radical capture and/or promotion of antioxidant protein biosynthesis are mechanisms that can be implicated in their neuroprotective actions. Due to their excellent pharmacological properties and the fact that they were not biologically explored in the past, one N-acylaminophenothiazine and one 1,4,5-dibenzo[b,f]thiadiazepine have been selected to develop two new series that are currently in progress.