Design and Synthesis of Edaravone Derivatives Containing 6‐(4‐aminophenyl)‐4,5‐dihydropyridazin‐3(2 <i>H</i> )‐one as Bifunctional Anti‐ischemic Stroke Agents

Ischemic stroke gravely endangers human health. To develop novel drugs with antiplatelet and neuroprotective functions for ischemic stroke, edaravone derivatives CT01-CT20, containing 6-(4-aminophenyl)-4,5-dihydropyridazin-3(2H)-one, were synthesized from materials like dimethyl butynedioate, ethyl acetoacetate, and diethyl 1,3-acetonedicarboxylate, via cyclization, hydrolysis, and condensation. Among them, CT16 exhibited outstanding antiplatelet activity (IC₅₀ = 6.72 µM), absent in edaravone. It also surpassed edaravone in 1,1-diphenyl-2-picrylhydrazyl radical scavenging (EC₅₀ = 30.80 µM) and protecting PC12 cells from H₂O₂ damage. In vivo, CT16 effectively reduced carotid artery thrombosis in rats and enhanced blood flow. In the middle cerebral artery occlusion reperfusion injury model, it shrank infarct size, improved neurological scores, increased cerebral blood flow, and lessened brain edema. Preliminary safety tests indicated CT16 didn't alter rat blood biochemistry or organ pathology, with a low bleeding risk as an antiplatelet agent. Molecular docking suggested it may inhibit phosphodiesterase 3A to achieve an antiplatelet effect. In conclusion, CT16 has both antiplatelet aggregation and neuroprotective effects and is a potential candidate compound for the treatment of ischemic stroke.