Design, Synthesis, and Biological Evaluation of Organic Nitrite (NO₂^–) Donors as Potential Anticerebral Ischemia Agents

The treatment of ischemic stroke
(IS) remains a big challenge in
clinics, and it is urgently needed to develop novel, safe, and effective
medicines against IS. Here, we report the design, synthesis, and biological
evaluation of organic NO2– donors as potential agents for the treatment of IS.
The representative compound 4a was able to slowly generate
low concentrations of NO2– by reaction with a thiol-containing nucleophile, and
the NO2– was selectively converted into NO under ischemic/hypoxia conditions
to protect primary rat neurons from oxygen–glucose deprivation
and recovery (OGD/R)-induced cytotoxicity by enhancing the Nrf2 signaling
and activating the NO/cGMP/PKG pathway. Treatment with 4a at 2 h before or after ischemia mitigated the ischemia/reperfusion-induced
brain injury in middle cerebral artery occlusion (MCAO) rats by producing
NO and enhancing Nrf2 signaling. Furthermore, 4a significantly
promoted endothelial cell proliferation and angiogenesis within the
ischemic penumbra. Our findings suggest that this type of NO2– donors,
like 4a, may be valuable to fight IS and other ischemic
diseases.