Synthesis and biological evaluation of benzopyran analogues bearing class III antiarrhythmic pharmacophores.

Abstract

We have synthesized a series of compounds combining the hydroxy-benzopyran ring of vitamin E with the methylsulfonylaminophenyl group of class III antiarrhythmic drugs, connected through tertiary amine moieties. Evaluation of the antiarrhythmic and antioxidant activity of the new compounds was carried out on isolated rat heart preparations using the non-recirculating Langendorff mode. The new analogues were present, at 10 microM concentration, during ischemia and reperfusion. Selected compounds were further studied by a conventional microelectrode method in order to get insight into their cellular mode of action. The most active compound, N-[4-[2-[[2-(3,4-dihydro-6-hydroxy-2,2,7,8-tetramethyl-2H-1-benzopyran-5-yl)ethyl] methylamine]ethyl]phenyl]methanesulfonamide (19a), reduces premature beats, prolongs QT and QRS intervals during ischemia and reperfusion, and reduces MDA content, leading to a fast recovery of the heart. In addition, it exhibits moderate class III antiarrhythmic action.

• Authors: Maria Koufaki, Christina Kiziridi, Panagiota Papazafiri, Athanasios Vassilopoulos, Andràs Varró, Zsolt Nagy, Attila Farkas, Alexandros Makriyannis
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 14 Issue 19 Pg. 6666-78 (Oct 01 2006) ISSN: 0968-0896 [Print] England
• PMID: 16782345 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Arrhythmia Agents
• Antioxidants
• Benzopyrans

Topics

• Action Potentials (drug effects)
• Animals
• Anti-Arrhythmia Agents (chemical synthesis, pharmacology)
• Antioxidants (chemical synthesis, pharmacology)
• Benzopyrans (chemical synthesis, pharmacology)
• Cardiac Complexes, Premature (drug therapy, physiopathology)
• Electrocardiography (drug effects)
• Heart (drug effects)
• In Vitro Techniques
• Male
• Microelectrodes
• Myocardial Ischemia (drug therapy, pathology)
• Myocardial Reperfusion Injury (drug therapy, pathology)
• Rabbits
• Rats
• Rats, Sprague-Dawley