title: Novel multi-functional nitrones for treatment of ischemic stroke.
abstract: Ischemic stroke resulting from obstruction of blood vessels is an enormous public health problem with urgent need for effective therapy. The co-administration of thrombolytic/antiplatelet agent and neuroprotective agent improves therapeutic efficacy and agent possessing both thrombolytic/antiplatelet and antiradical activities provides a promising strategy for the treatment of ischemic stroke. We have previously reported a novel compound, namely TBN, possessing both antiplatelet and antiradical activities, showed significant neuroprotective effect in a rat stroke model. We herein report synthesis of a series of new pyrazine derivatives, and evaluation of their biological activities. Their mechanisms of action were also investigated. Among these new derivatives, compound 21, armed with two nitrone moieties, showed the greatest neuroprotective effects in vitro and in vivo. Compound 21 significantly inhibited ADP-induced platelet aggregation. In a cell free antiradical assay, compound 21 was the most effective agent in scavenging the three most damaging radicals, namely (·)OH, O(2)(·-) and ONOO(-).
authors.affiliation: Institute of New Drug Research and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine, Jinan University College of Pharmacy, Guangzhou 510632, China.
authors.forename: Yewei
authors.initials: Y
authors.lastname: Sun
authors.forename: Gaoxiao
authors.initials: G
authors.lastname: Zhang
authors.forename: Zaijun
authors.initials: Z
authors.lastname: Zhang
authors.forename: Pei
authors.initials: P
authors.lastname: Yu
authors.forename: Haijing
authors.initials: H
authors.lastname: Zhong
authors.forename: Jing
authors.initials: J
authors.lastname: Du
authors.forename: Yuqiang
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D016166:Free Radical Scavengers / Q000378:metabolism; D008297:Male; D015394:Molecular Structure; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D009589:Nitrogen Oxides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000188:drug therapy*; D013329:Structure-Activity Relationship
chemical_list: D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D009589:Nitrogen Oxides; C015388:nitrones