Discovery of Novel Hybrids of Edaravone and 6‐Phenyl‐4,5‐dihydropyridazin‐3(2H)‐one with Antiplatelet Aggregation and Neuroprotection for Ischemic Stroke Treatment

• Published in: Chemistry & biodiversity Vol. 21; no. 5; pp. e202400110 - n/a
• Main Authors: Li, Yi, He, Jieying, Luo, Bilan, Yu, Qinyang, Cai, Ting, Li, Yong, Fan, Lingling, Zhou, Xunrong, Tang, Lei
• Format: Journal Article
• Language: English
• Published: Switzerland Wiley Subscription Services, Inc 01.05.2024
• Subjects: 6-phenyl-4,5-dihydropyridazin-3(2H)-one; Adenosine diphosphate; ADP; Aggregation; Animals; anti-platelet aggregation; Arachidonic acid; Aspirin; cerebral ischemia/reperfusion; Drug Discovery; Edaravone; Edaravone - chemistry; Edaravone - pharmacology; Ferric chloride; Hybrids; Ischemia; Ischemic Stroke - drug therapy; Ischemic Stroke - metabolism; Ischemic Stroke - pathology; Male; Mice; Molecular docking; Molecular Docking Simulation; Molecular Structure; Neuroprotection; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Oxidative stress; Oxidative Stress - drug effects; Platelet aggregation; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - chemical synthesis; Platelet Aggregation Inhibitors - chemistry; Platelet Aggregation Inhibitors - pharmacology; Platelets; Pyridazines - chemistry; Pyridazines - pharmacology; Rats; Rats, Sprague-Dawley; Reperfusion; Stroke; Structure-Activity Relationship; Thromboembolism; Thrombosis; cerebral ischemia/reperfusion; Edaravone; anti-platelet aggregation; 6-phenyl-4,5-dihydropyridazin-3(2H)-one; neuroprotection
• ISSN: 1612-1872; 1612-1880
• DOI: 10.1002/cbdv.202400110

Drugs with anti‐platelet aggregation and neuroprotection are of great significance for the treatment of ischemic stroke. A series of edaravone and 6‐phenyl‐4,5‐dihydropyridazin‐3(2H)‐one hybrids were designed and synthesized. Among them, 6g showed the most effective cytoprotective effect against oxygen‐glucose deprivation/reoxygenation‐induced damage in BV2 cells and an excellent inhibitory effect on platelet aggregation induced by adenosine diphosphate and arachidonic acid. Additionally, 6g could prevent thrombosis caused by ferric chloride in rats and pose a lower risk of causing bleeding compared with aspirin. It provides better protection against ischemia/reperfusion injury in rats compared with edaravone and alleviates the oxidative stress related to cerebral ischemia/reperfusion by increasing the GSH and SOD levels and decreasing the MDA concentration. Finally, molecular docking results showed that 6g probably acts on PDE3 A and plays an anti‐platelet aggregation effect. Overall, 6g could be a potential candidate compound for the treatment of ischemic stroke.