Heteroarylnitrones as Drugs for Neurodegenerative Diseases: Synthesis, Neuroprotective Properties, and Free Radical Scavenger Properties

New 1,2,4-thiadiazolylnitrones and furoxanylnitrones were developed and evaluated as neuroprotective agents on a human neuroblastoma (SH-SY5Y) cells model. They inhibited at low micromolar concentrations the oxidative damage and the death induced by exposure to hydrogen peroxide. These heteroarylnitrones showed excellent peroxyl free radical absorbance capacities, analyzed by oxygen radical absorbance capacity (ORAC) assay with fluorescein as the fluorescent probe, ranging from 1.5- to 16.5-fold the value of the reference nitrone, R-phenyl-N-tert-butylnitrone (PBN). The electron spin resonance spectroscopy (ESR) demonstrated the ability of these derivatives to directly trap and stabilize oxygen, carbon, and sulfur-centered free radicals. These results demonstrated the potential use of these heteroarylnitrones as neuroprotective agents in preventing the death of cells exposed to enhanced oxidative stress and damage.The authors thank Collaborative Project UdelaR (Uruguay), CSIC (Spain) (Grant 2006UY0009), and Neuropharma S.A (Madrid, Spain). W.P. thanks Collaborative Project (Grant 2006UY0009) and CSIC (UdelaR) for fellowships