Jingxia Zhang

Background: The oxidative stress and neuroinflammation are important factors in acute ischemic stroke (AIS). Our former study showed the 1,2,4‐ triazole derivative (SYS18) had obviously neuroprotection by anti‐ oxidative stress on rat middle cerebral artery occlusion (MCAO) model.Aim: In this study, we continue to investigate its neuroprotection by anti‐inflammatory effects and protecting BBB integrity in AIS.Methods and Results: First, its effect on acute inflammation was evaluated by the mice model of increased peritoneal capillary permeability. Then, the MCAO cerebral edema models were built to evaluate its neuroprotection by reducing the neurological score, cerebral edema, improving the biochemical indicators, and pathological damage of brain tissue. At the same time, its protection on blood–brain barrier (BBB) integrity was proved by decreasing the BBB permeability and inhibiting glycocalyx degradation and regulating the BBB tight junction proteins expression of matrix metalloproteinase‐ 9 (MMP‐ 9) and claudin‐ 5 in brain tissue. Meanwhile, pharmacokinetic experiments showed that the compound had good BBB penetration. It has some advantages in the intensity of efficacy compared with the marketed drug edaravone.Conclusion: Based on these findings, SYS18 has a strong potential to become a neuroprotectant in the future.

In this study, 22 novel compounds were designed and synthesized by acetamide bridge chains, among which 5 a–5 k were monosubstituted compounds, and 6 a–6 k were disubstituted. A series of biological evaluations was then carried out to determine the carbonic anhydrase inhibitory activity, neuroprotective effects and cytotoxicity of 5 a–5 k and 6 a–6 k. The results showed that some compounds could protect PC12 cells from sodium nitroprusside (SNP)‐induced damage. In terms of the neuroprotection and inhibitory activity against carbonic anhydrase II, monosubstituted compounds were better than disubstituted. Compound 5 c exhibited better protective effect in PC12 cells than that of edaravone, and 5 c also showed less cytotoxicity. In addition, compound 5 c was found to be the most effective selective carbonic anhydrase II inhibitor (IC₅₀=16.7 nM, CAI/CAII=54.3), which was similar to the inhibitory effect of acetazolamide. Moreover, the selectivity of compound 5 c was better than that of acetazolamide (IC₅₀=12.0 nM, CAI/CAII=20.8). Molecular docking presented that the binding effect of compound 5 c with carbonic anhydrase II was superior to that of 5 c with carbonic anhydrase I and IX, which was consistent with the inhibitory results. Based on above findings, compound 5 c may be a potential candidate for selective carbonic anhydrase II inhibitor, and it had obviously neuroprotective effect and great advantages in drug safety.