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

Escobar-Peso A, Martínez-Alonso E et al.  Eur J Med Chem. 2024 Feb 15;266:116133. doi: 10.1016/j.ejmech.2024.116133. Epub 2024 Jan 9. PMID: 38218126

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. 

Funding: A.A. and J.M.-C thank the Community of Madrid for support. This work is part of the MINA-CM program (number S2022/BMD-7236), funded by the call for the implementation of programs of R&D activities between research groups of the Community of Madrid in Biomedicine 2022 (Order 1171/2022). This work has been also co-funded by Instituto de Salud Carlos III through the projects PI22/01381 and RD21/0006/0019 and European Union granted to A.A, and the contract IFI18/ 00011 to A.E.-P.