Synthesis and biological evaluation of benzopyran analogues bearing class III antiarrhythmic pharmacophores.
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.
Koufaki
Maria
M
Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, 48 Vas. Constantinou Avenue, 116 35 Athens, Greece. mkoufa@eie.gr
Kiziridi
Christina
C
Papazafiri
Panagiota
P
Vassilopoulos
Athanasios
A
Varró
Andràs
A
Nagy
Zsolt
Z
Farkas
Attila
A
Makriyannis
Alexandros
A
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D000975:Antioxidants / Q000138:chemical synthesis* / Q000494:pharmacology*; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000494:pharmacology*; D005117:Cardiac Complexes, Premature / Q000188:drug therapy / Q000503:physiopathology; D004562:Electrocardiography / Q000187:drug effects; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008839:Microelectrodes; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000473:pathology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley
D000889:Anti-Arrhythmia Agents; D000975:Antioxidants; D001578:Benzopyrans