Synthesis and evaluation of in vivo activity of diphenylhydantoin basic derivatives

Eur J Med Chem. 2004 Dec;39(12):1013-27. doi: 10.1016/j.ejmech.2004.05.008.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Arrhythmia Agents / chemical synthesis
  • Anti-Arrhythmia Agents / pharmacology
  • Anticonvulsants / chemical synthesis
  • Anticonvulsants / pharmacology
  • Antihypertensive Agents / chemical synthesis
  • Antihypertensive Agents / pharmacology
  • Electrocardiography / drug effects
  • Heart Rate / drug effects
  • Male
  • Mice
  • Molecular Structure
  • Phenytoin / analogs & derivatives*
  • Phenytoin / chemical synthesis
  • Phenytoin / pharmacology
  • Phenytoin / toxicity
  • Postural Balance / drug effects
  • Rats
  • Rats, Wistar

Substances

  • Anti-Arrhythmia Agents
  • Anticonvulsants
  • Antihypertensive Agents
  • Phenytoin