| Summary: | Herein, we report the neuroprotective and antioxidant activity of 1,1′-biphenyl nitrones (<b>BPNs</b>) <b>1</b>–<b>5</b> as α-phenyl-<i>N</i>-<i>tert</i>-butylnitrone analogues prepared from commercially available [1,1′-biphenyl]-4-carbaldehyde and [1,1′-biphenyl]-4,4′-dicarbaldehyde. The neuroprotection of <b>BPNs</b><b>1</b>-<b>5</b> has been measured against oligomycin A/rotenone and in an oxygen–glucose deprivation in vitro ischemia model in human neuroblastoma SH-SY5Y cells. Our results indicate that <b>BPNs 1</b>–<b>5</b> have better neuroprotective and antioxidant properties than α-phenyl-<i>N</i>-<i>tert</i>-butylnitrone (<b>PBN</b>), and they are quite similar to <i>N</i>-acetyl-L-cysteine (<b>NAC</b>), which is a well-known antioxidant agent. Among the nitrones studied, homo-bis-nitrone <b>BPHBN5</b>, bearing two <i>N</i>-<i>tert</i>-Bu radicals at the nitrone motif, has the best neuroprotective capacity (EC<sub>50</sub> = 13.16 ± 1.65 and 25.5 ± 3.93 μM, against the reduction in metabolic activity induced by respiratory chain blockers and oxygen–glucose deprivation in an in vitro ischemia model, respectively) as well as anti-necrotic, anti-apoptotic, and antioxidant activities (EC<sub>50</sub> = 11.2 ± 3.94 μM), which were measured by its capacity to reduce superoxide production in human neuroblastoma SH-SY5Y cell cultures, followed by mononitrone <b>BPMN3</b>, with one <i>N</i>-Bn radical, and <b>BPMN2</b>, with only one <i>N</i>-<i>tert</i>-Bu substituent. The antioxidant activity of <b>BPNs</b><b>1</b>-<b>5</b> has also been analyzed for their capacity to scavenge hydroxyl free radicals (82% at 100 μM), lipoxygenase inhibition, and the inhibition of lipid peroxidation (68% at 100 μM). Results showed that although the number of nitrone groups improves the neuroprotection profile of these <b>BPNs</b>, the final effect is also dependent on the substitutent that is being incorporated. Thus, <b>BPNs</b> bearing <i>N</i>-<i>tert</i>-Bu and <i>N</i>-Bn groups show better neuroprotective and antioxidant properties than those substituted with Me. All these results led us to propose homo-<i>bis</i>-nitrone <b>BPHBN5</b> as the most balanced and interesting nitrone based on its neuroprotective capacity in different neuronal models of oxidative stress and in vitro ischemia as well as its antioxidant activity.
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