Synthesis and SAR-study for novel arylpiperazine derivatives of 5-arylidenehydantoin with α₁-adrenoceptor antagonistic properties.
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)<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 α(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).
Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland.
Jadwiga
J
Handzlik
Ewa
E
Szymańska
Renata
R
Wójcik
Anna
A
Dela
Magdalena
M
Jastrzębska-Więsek
Janina
J
Karolak-Wojciechowska
Andrzej
A
Fruziński
Agata
A
Siwek
Barbara
B
Filipek
Katarzyna
K
Kieć-Kononowicz
D058668:Adrenergic alpha-1 Receptor Antagonists / Q000138:chemical synthesis* / Q000737:chemistry; D000818:Animals; D018360:Crystallography, X-Ray; D006827:Hydantoins / Q000138:chemical synthesis / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D000077489:Piperazine; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry*; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
D058668:Adrenergic alpha-1 Receptor Antagonists; D006827:Hydantoins; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; D000077489:Piperazine