Synthesis and SAR-study for novel arylpiperazine derivatives of 5-arylidenehydantoin with α1-adrenoceptor antagonistic properties

Abstract The study is focused on a series of 5-arylidenehydantoin derivatives with a phenylpiperazine-hydroxypropyl fragment at N3 of the hydantoin ring. The compounds were assessed on their affinity for α 1 -adrenoceptors and evaluated in functional bioassays for their antagonistic properties. Crystal structures of ( Z )-5-(4-chlorobenzylidene)-3-(3-(4-(2-ethoxyphenyl)piperazin-1-yl)-2-hydroxypropyl)imidazolidine-2,4-dione ( 7 ) and hydrochloride of ( Z )-5-(4-chlorobenzylidene)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)imidazolidine-2,4-dione ( 10a ) were solved using the X-ray diffraction method. Classical molecular mechanics (MMFFs force field, MCMM, MacroModel) were used to predict 3D structure of compounds 5a – 18a using a crystal structure of 7 . SAR analysis was performed on the basis of Barbaro’s pharmacophore model and structural properties of previously investigated α 1 -adrenoceptor antagonists possessing a hydantoin fragment. Most of the compounds exhibited significant affinities for α 1 -ARs in nanomolar range (40–290 nM). The highest activities ( K i 1 -affinities as follows: 3,4-di CH 3 O>2,4-di CH 3 O>4-Cl>2,3-di CH 3 O>H>4-N(CH 3 ) 2 .