title: Synthesis and evaluation of in vivo activity of diphenylhydantoin basic derivatives.
abstract: During the search for antiarrhythmic agents among amide derivatives of phenytoin, compound 7 {3-ethyl-1-[2-hydroxy-3-(4-phenyl-piperazin-1-yl)-propyl]-2,4-dioxo-5,5-diphenyl-imidazolidine} was selected as it showed antiarrhythmic as well as antihypertensive activity. Treating this compound as a lead, new derivatives 8-19 were synthesised, differing in piperazine phenyl ring substitution (2-, 3-, 4-Cl, 2-CH3O) as well as in hydantoin N3 alkyl chain (ethyl, ethyl acetate or ethyl 2-propionate). The obtained compounds in form of hydrochlorides 7a-19a were examined for prophylactic antiarrhythmic and antihypertensive properties. Compounds containing ethyl 2-propionate moiety (17a, 18a) exhibited the highest antihypertensive properties. Water-soluble compounds, containing 2-methoxyphenylpiperazine group (11a, 19a), showed strong antiarrhythmic properties in adrenaline-induced arrhythmia; compound 9a {1-[3-(4-(3-chloro-phenyl)-piperazin-1-yl)- 2-hydroxy-propyl]- 3-ethyl-2,4-dioxo-5,5-diphenyl-imidazolidine hydrochloride} exhibited the highest antiarrhythmic activity in barium chloride arrhythmia model.
authors.affiliation: Department of Technology and Biotechnology of Drugs, Collegium Medicum of the Jagiellonian University, Medyczna 9, Pl 30-688 Kraków, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Dylag
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Zygmunt
authors.forename: Dorota
authors.initials: D
authors.lastname: Maciag
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Handzlik
authors.forename: Marek
authors.initials: M
authors.lastname: Bednarski
authors.forename: Barbara
authors.initials: B
authors.lastname: Filipek
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kieć-Kononowicz
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis / Q000494:pharmacology; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000494:pharmacology; D004562:Electrocardiography / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010672:Phenytoin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D004856:Postural Balance / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000889:Anti-Arrhythmia Agents; D000927:Anticonvulsants; D000959:Antihypertensive Agents; D010672:Phenytoin