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, alpha-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.
Porcal
Williams
W
Departamento de Química Orgánica, Facultad de Ciencias-Facultad de Química, Universidad de la República, Montevideo, Uruguay.
Hernández
Paola
P
González
Mercedes
M
Ferreira
Ana
A
Olea-Azar
Claudio
C
Cerecetto
Hugo
H
Castro
Ana
A
D000818:Animals; D001665:Binding Sites; D002470:Cell Survival / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004578:Electron Spin Resonance Spectroscopy; D016166:Free Radical Scavengers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D019636:Neurodegenerative Diseases / Q000188:drug therapy*; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000032:analysis; D012680:Sensitivity and Specificity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D006571:Heterocyclic Compounds; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; C029217:phenyl-N-tert-butylnitrone; D006861:Hydrogen Peroxide