Orally Bioavailable Metal Chelators and Radical Scavengers: Multifunctional Antioxidants for the Coadjutant Treatment of Neurodegenerative Diseases

Neurodegenerative
diseases are associated with oxidative stress
that is induced by the presence of reactive oxygen species and the
abnormal cellular accumulation of transition metals. Here, a new series
of orally bioavailable multifunctional antioxidants (MFAO-2s) possessing
a 2-diacetylamino-5-hydroxypyrimidine moiety is described. These MFAO-2s
demonstrate both free radical and metal attenuating properties that
are similar to the original published MFAO-1s that are based on 1-N,N′-dimethylsulfamoyl-1-4-(2-pyrimidyl)­piperazine.
Oral bioavailability studies in C57BL/6 mice demonstrate that the
MFAO-2s accumulate in the brain at significantly higher levels than
the MFAO-1s while achieving similar neural retina levels. The MFAO-2s
protect human neuroblastoma and retinal pigmented epithelial cells
against hydroxyl radicals in a dose-dependent manner by maintaining
cell viability and intracellular glutathione levels. The MFAO-2s outperform
clioquinol, a metal attenuator that has been investigated for the
treatment of Alzheimer’s disease.