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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(-).
AuthorsYewei Sun, Gaoxiao Zhang, Zaijun Zhang, Pei Yu, Haijing Zhong, Jing Du, Yuqiang Wang
JournalBioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 20 Issue 12 Pg. 3939-45 (Jun 15 2012) ISSN: 1464-3391 [Electronic] England
PMID22579617 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2012 Elsevier Ltd. All rights reserved.
Chemical References
  • Free Radical Scavengers
  • Neuroprotective Agents
  • Nitrogen Oxides
  • nitrones
Topics
  • Animals
  • Dose-Response Relationship, Drug
  • Drug Design
  • Free Radical Scavengers (metabolism)
  • Male
  • Molecular Structure
  • Neurons (cytology, drug effects)
  • Neuroprotective Agents (chemistry, pharmacology, therapeutic use)
  • Nitrogen Oxides (chemistry, pharmacology, therapeutic use)
  • Platelet Aggregation (drug effects)
  • Rats
  • Rats, Sprague-Dawley
  • Stroke (drug therapy)
  • Structure-Activity Relationship

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