Design, synthesis, and biological evaluation of novel ebselen-chalcone hybrids as multifunctional neuroprotective agents for ischemic stroke

Ischemic stroke is a multifactorial neurological disorder characterized by oxidative stress, neuroinflammation, and mitochondrial dysfunction. Currently, effective neuroprotective agents for treating ischemic stroke remain limited. To integrate the glutathione peroxidase (GPx)-mimicking activity of ebselen with the antioxidant and anti-inflammatory properties of chalcones, a total of 67 ebselen-chalcone hybrids were rationally designed and synthesized. Biological evaluation identified B21 as an initial lead compound with improved neuroprotective activity and reduced cytotoxicity compared to ebselen, as reflected by an enhanced selectivity index (SI > 6.37 vs 2.43). Subsequent structural optimization led to the identification of C13, which exhibited superior neuroprotective and anti-inflammatory activities with a markedly improved safety (SI > 50.31). Furthermore, in vivo bioassay demonstrated that C13 showed good tolerability and exerted significant neuroprotective effects in a middle cerebral artery occlusion (MCAO) model, comparable to the positive control edaravone. Mechanistic studies revealed that C13 effectively reduced intracellular reactive oxygen species accumulation and preserved mitochondrial membrane potential, primarily through activation of the Nrf2/HO-1 signaling pathway. Overall, this study highlights the effectiveness of an ebselen-based molecular hybridization strategy and identifies C13 as a promising lead compound for ischemic stroke therapy.