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

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-1. 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-pharma-cophore model using Discovery studio 2.1 programs and their docking into optimized alpha(1)-AR homology models as alpha(1)-AR antagonist showed high-docking score and fit values. The experimental in vitro vasodilation activity of compounds 3a-1 was consistent with the molecular modeling. (C) 2010 Elsevier Masson SAS. All rights reserved.