Synthesis, antioxidant and neuroprotective analysis of diversely functionalized α-aryl-N-alkyl nitrones as potential agents for ischemic stroke therapy

Abstract

Herein, we report the synthesis, antioxidant and biological evaluation of 32 monosubstituted α-arylnitrones derived from α-phenyl-tert-butyl nitrone (PBN) in the search for neuroprotective compounds for ischemic stroke therapy, trying to elucidate the structural patterns responsible for their neuroprotective activity. Not surprisingly, the N-tert-butyl moiety plays beneficious role in comparison to other differently N-substituted nitrone groups. It seems that electron donor substituents at the ortho position and electron withdrawing substituents at the meta position of the aryl ring induce good neuroprotective activity. As a result, (Z)-N-tert-butyl-1-(2-hydroxyphenyl)methanimine oxide (21a) and (Z)-N-tert-butyl-1-(2-(prop-2-yn-1-yloxy)phenyl)methanimine oxide (24a) showed a significant increase in neuronal viability in an experimental ischemia model in primary neuronal cultures, and induced neuroprotection and improved neurodeficit score in an in vivo model of transient cerebral ischemia. These results showed that nitrones 21a and 24a are new effective small and readily available antioxidants, and suitable candidates for further structure optimization in the search for new phenyl-derived nitrones for the treatment of ischemic stroke and related diseases.