Sulfonamide-flavonoid analogue SG16 shows promise as a novel anti-inflammatory agent for ischemic stroke treatment.

Ischemic stroke is the third most important cause of death globally and is the foremost cause of disability. Currently, rt-PA, the only clinically approved drug, is limited by a 4.5 h time window and high bleeding risk, and its applicable population is less than 10%. Studies have shown that oxidative stress is the core mechanism of neural injury after ischemia. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a neuroprotective role in cerebral ischemia-reperfusion injury (CIRI) by activating antioxidant genes. Based on the advantages of the sulfonamide group and the antioxidant properties of flavonoid compounds, SG16 was designed and synthesized through the fragment grafting strategy. This study demonstrated that SG16 could significantly improve neurological motor function, reduce the volume of brain ischemia, and effectively reduce the loss of neurons in ischemic stroke. SG16 enhances Nrf2 pathway activation and its downstream antioxidant responses, leading to a notable increase in the expression of heme oxygenase-1 (HO-1) and glutamate-cysteine ligase regulatory subunit (GCLM). SG16 concurrently suppresses microglial activation and the secretion of neuroinflammatory factors. These results demonstrate that SG16 exerts its antioxidant, anti-inflammatory, and neuroprotective effects primarily through the activation of the Nrf2 signaling pathway in vivo. Therefore, when developing new drugs for treating stroke, SG16 can be regarded as a potential alternative compound.