Structure-activity studies on the protection of Trimetazidine derivatives modified with nitroxides and their precursors from myocardial ischemia-reperfusion injury.

Abstract

Trimetazidine, the known anti-anginal and anti-ischemic drug, was modified by pyrroline and tetrahydropyridine nitroxides and their hydroxylamine and sterically hindered secondary amine precursors. The synthesized new compounds proved to be better superoxide scavenger molecules compared to the parent Trimetazidine in an in vitro experiment. This reactive oxygen species (ROS) scavenging activity was further supported by ischemia/reperfusion (I/R) studies on Langendorff-perfused rat hearts pretreated with Trimetazidine and with the modified Trimetazidine derivatives before ischemia. Two of the investigated compounds, containing 2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrole and 4-phenyl-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrole substituents on the piperazine ring, provided significant protection from the cardiac dysfunction caused by I/R. The protective effect could be attributed to the combined anti-ischemic and antioxidant effects.

• Authors: Tamás Kálai, Mahmood Khan, Mária Balog, Vijay Kumar Kutala, Periannan Kuppusamy, Kálmán Hideg
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 14 Issue 16 Pg. 5510-6 (Aug 15 2006) ISSN: 0968-0896 [Print] England
• PMID: 16697647 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Nitrogen Oxides
• Piperazines
• Reactive Oxygen Species
• Vasodilator Agents
• Piperazine
• Trimetazidine

Topics

• Animals
• Antioxidants (chemistry, pharmacology)
• Myocardial Reperfusion Injury (complications, pathology, prevention & control)
• Nitrogen Oxides (chemistry)
• Piperazine
• Piperazines (chemistry)
• Rats
• Rats, Sprague-Dawley
• Reactive Oxygen Species (chemistry, metabolism)
• Structure-Activity Relationship
• Trimetazidine (analogs & derivatives, pharmacology)
• Vasodilator Agents (chemistry, pharmacology)