Regioselective synthesis and molecular modeling study of vasorelaxant active 7,9-dioxa-1,2-diaza-spiro[4.5]dec-2-ene-6,10-diones

Adel S. Girgis, Nasser S.M. Ismail, Hanaa Farag, Wafaa I. El-Eraky, Dalia O. Saleh, Srinivasa Tala, Alan R. Katritzky

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

Nitrilimines (PhC-:N+:NR′) generated in situ from hydrazonoyl chlorides 2a,b reacted regioselectively with 5-arylidene-2,2-dimethyl[1,3]dioxane-4,6-diones 1a-f to afford 1,3,4-triaryl-8,8-dimethyl-7,9-dioxa-1,2-diaza-spiro[4.5]dec-2-ene-6,10-diones 3a-l. In vitro vasodilation activity screening of the synthesized compounds using isolated thoracic aortic rings of male Wister rats pre-contracted with norepinephrine hydrochloride revealed considerable vasodilation activity; compounds 3f and 3j had IC50 (concentration necessary for 50% reduction of maximal norepinephrine hydrochloride induced contracture) of 0.325, 0.321 mM, respectively. Molecular modeling, including fitting to a 3D-pharmacophore model using Discovery studio 2.1 programs and their docking into optimized α1-AR homology models as α1-AR antagonist showed high-docking score and fit values. The experimental in vitro vasodilation activity of compounds 3a-l was consistent with the molecular modeling.

Original languageEnglish (US)
Pages (from-to)4229-4238
Number of pages10
JournalEuropean Journal of Medicinal Chemistry
Volume45
Issue number9
DOIs
StatePublished - Sep 1 2010

Keywords

  • 5-Arylidene-2,2-dimethyl[1,3]dioxane-4,6-diones
  • 7,9-Dioxa-1,2-diaza-spiro[4.5]dec-2-ene-6,10-diones
  • Dipolar cycloaddition
  • Hydrazonoyl halides
  • Molecular modeling
  • Vasodilation

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