title: 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.affiliation: Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, 48 Vas. Constantinou Avenue, 116 35 Athens, Greece. mkoufa@eie.gr
authors.forename: Maria
authors.initials: M
authors.lastname: Koufaki
authors.forename: Christina
authors.initials: C
authors.lastname: Kiziridi
authors.forename: Panagiota
authors.initials: P
authors.lastname: Papazafiri
authors.forename: Athanasios
authors.initials: A
authors.lastname: Vassilopoulos
authors.forename: Andràs
authors.initials: A
authors.lastname: Varró
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Nagy
authors.forename: Attila
authors.initials: A
authors.lastname: Farkas
authors.forename: Alexandros
authors.initials: A
authors.lastname: Makriyannis
mesh_terms: 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
chemical_list: D000889:Anti-Arrhythmia Agents; D000975:Antioxidants; D001578:Benzopyrans