title: Discovery of 3-n-butyl-2,3-dihydro-1H-isoindol-1-one as a potential anti-ischemic stroke agent.
abstract: To develop novel anti-ischemic stroke agents with better therapeutic efficacy and bioavailability, we designed and synthesized a series of 3-alkyl-2,3-dihydro-1H-isoindol-1-ones compounds (3a-i) derivatives, one of which (3d) exhibited the strongest inhibitory activity for the adenosine diphosphate-induced and arachidonic acid-induced platelet aggregation. This activity is superior to that of 3-n-butylphthalide and comparable with aspirin and edaravone. Meanwhile, 3d not only exhibited a potent activity in scavenging free radicals and improving the survival of HT22 cells against the reactive oxygen species-mediated cytotoxicity in vitro but also significantly attenuated the ischemia/reperfusion-induced oxidative stress in ischemic rat brains. Results from transient middle cerebral artery occlusion and permanent middle cerebral artery occlusion model, indicated that 3d could significantly reduce infarct size, improve neurobehavioral deficits, and prominently decrease attenuation of cerebral damage. Most importantly, 3d possessed a very high absolute bioavailability and was rapidly distributed in brain tissue to keep high plasma drug concentration for the treatment of ischemic strokes. In conclusion, our findings suggest that 3-alkyl-2,3-dihydro-1H-isoindol-1-ones, a novel series of compounds, might be candidate drugs for the treatment of acute ischemic strokes, and 3d may be a promising therapeutic agent for the primary and secondary prevention of ischemic stroke.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China.
authors.forename: Zujian
authors.initials: Z
authors.lastname: Lan
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Xu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China.
authors.forename: Wenkai
authors.initials: W
authors.lastname: Xu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China.
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China.
authors.forename: Zengrong
authors.initials: Z
authors.lastname: Liang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China.
authors.forename: Xuefei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China.
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China.
authors.forename: Chunshun
authors.initials: C
authors.lastname: Zhao
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D000983:Antipyrine / Q000031:analogs & derivatives / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001572:Benzofurans / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002351:Carrageenan; D002460:Cell Line; D004195:Disease Models, Animal; D000077553:Edaravone; D005343:Fibrinolytic Agents / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000097:blood / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control* / Q000523:psychology; D054833:Isoindoles / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000097:blood / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control* / Q000523:psychology; D013329:Structure-Activity Relationship; D013927:Thrombosis / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control; D014018:Tissue Distribution
chemical_list: C000606307:3-n-butyl-2,3-dihydro-1H-isoindol-1-one; D000975:Antioxidants; D001572:Benzofurans; D005343:Fibrinolytic Agents; D054833:Isoindoles; D018696:Neuroprotective Agents; D010975:Platelet Aggregation Inhibitors; C027125:3-n-butylphthalide; D002351:Carrageenan; D000077553:Edaravone; D000983:Antipyrine
keywords: 3-alkyl-2,3-dihydro-1H-isoindol-1-ones; ischemia/reperfusion; middle cerebral artery occlusion; platelet aggregation; stroke