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-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 IC(50) (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 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-l was consistent with the molecular modeling.
Girgis
Adel S
AS
Pesticide Chemistry Department, National Research Centre, Dokki, Cairo 12622, Egypt. girgisas10@yahoo.com
Ismail
Nasser S M
NS
Farag
Hanaa
H
el-Eraky
Wafaa I
WI
Saleh
Dalia O
DO
Tala
Srinivasa R
SR
Katritzky
Alan R
AR
D058668:Adrenergic alpha-1 Receptor Antagonists; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D008297:Male; D008958:Models, Molecular; D011487:Protein Conformation; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000737:chemistry; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013237:Stereoisomerism; D013379:Substrate Specificity; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D058668:Adrenergic alpha-1 Receptor Antagonists; D018340:Receptors, Adrenergic, alpha-1; D013141:Spiro Compounds; D014665:Vasodilator Agents