TY - JOUR
T1 - Regioselective synthesis and molecular modeling study of vasorelaxant active 7,9-dioxa-1,2-diaza-spiro[4.5]dec-2-ene-6,10-diones
AU - Girgis, Adel S.
AU - Ismail, Nasser S.M.
AU - Farag, Hanaa
AU - El-Eraky, Wafaa I.
AU - Saleh, Dalia O.
AU - Tala, Srinivasa R.
AU - Katritzky, Alan R.
PY - 2010/9
Y1 - 2010/9
N2 - 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.
AB - 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.
KW - 5-Arylidene-2,2-dimethyl[1,3]dioxane-4,6-diones
KW - 7,9-Dioxa-1,2-diaza-spiro[4.5]dec-2-ene-6,10-diones
KW - Dipolar cycloaddition
KW - Hydrazonoyl halides
KW - Molecular modeling
KW - Vasodilation
UR - http://www.scopus.com/inward/record.url?scp=77955551434&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77955551434&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2010.06.018
DO - 10.1016/j.ejmech.2010.06.018
M3 - Article
C2 - 20615586
AN - SCOPUS:77955551434
SN - 0223-5234
VL - 45
SP - 4229
EP - 4238
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
IS - 9
ER -