Design and synthesis of novel indole and indazole-piperazine pyrimidine derivatives with anti-inflammatory and neuroprotective activities for ischemic stroke treatment

Microglia-mediated neuroinflammation plays an important role in ischemic stroke (IS). In this work, a series of novel indole and indazole-piperazine pyrimidine derivatives with anti-neuroinflammatory and neuroprotective activities were designed and synthesized for treatment of IS. Among these compounds, 5j displayed the most attractive cytoprotective effect against oxygen-glucose deprivation/reoxygenation (OGD/R)-induced damage in BV2 cells. Meanwhile, it significantly ameliorated the release of inflammatory mediators, including tumor ne-crosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), IL-6, nitric oxide (NO) and prostaglandin E2 (PGE2), from lipo-polysaccharide (LPS)-induced BV2 cells. Moreover, 5j can decrease the release of TNF-alpha and IL-1 beta form LPS-induced mouse brain neuroinflammation model. As a potent inhibitor against both cyclooxygenase-2 (COX-2, IC50 = 92.54 nM) and 5-lipoxygenase (5-LOX, IC50 = 41.86 nM), 5j inhibited the M1 phenotype polarization of microglia and promoted the M2 phenotype polarization of microglia. Additionally, 5j exhibited remarkable neuroprotection in middle cerebral artery occlusion (MCAO) rats by reducing their infarct volumes and neuro-logical deficit scores. In conclusion, 5j has the potential for the treatment of stroke as an anti-inflammatory and neuroprotective agent.

Automated summary

In this study, a series of novel indole and indazole-piperazine pyrimidine derivatives were designed and synthesized. Compound 5j displayed strong anti-neuroinflammatory and neuroprotective effects in cell and animal models, making it a potential treatment for stroke.