Synthesis and SAR-study for novel arylpiperazine derivatives of 5-arylidenehydantoin with ¦Á₁-adrenoceptor antagonistic properties

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• 作者：Jadwiga H ; zlik ; Ewa Szyma¨½ska ; Renata W¨®jcik ; Anna Dela ; Magdalena Jastrz?bska-Wi?sek ; Janina Karolak-Wojciechowska ; Andrzej Fruzi¨½ski ; Agata Siwek ; Barbara Filipek ; Katarzyna Kie?-Kononowicz
• 关键词：Arylpiperazine derivatives ; Hydantoin derivatives ; Arylidenehydantoin ; Mitsunobu reaction ; Alpha-1 adrenoceptor antagonist ; Microwave irradiation
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 出版时间：15 July, 2012
• 年：2012
• 卷：20
• 期：14
• 页码：4245-4257
• 全文大小：932 K

文摘

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 ¦Á₁-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 ¦Á₁-adrenoceptor antagonists possessing a hydantoin fragment. Most of the compounds exhibited significant affinities for ¦Á₁-ARs in nanomolar range (40-290 nM). The highest activities (K_i <75 nM) were observed for compounds possessing a 2-alkoxyphenylpiperazine fragment and two methoxy substituents at the benzylidene moiety. The results indicated that chemical properties, number and positions of substituents at the 5-arylidene fragment influenced the power of ¦Á₁-affinities as follows: 3,4-di CH₃O>2,4-di CH₃O>4-Cl>2,3-di CH₃O>H>4-N(CH₃)₂.