title: Synthesis, vasorelaxant activity, and molecular modeling study of some new phthalazine derivatives.
abstract: New phthalazine-based vasodilators were synthesized through the chloroacylation of the starting compound 1-hydrazinophthalazine 4 to give the two key intermediates 5 and 7. These intermediates were used to alkylate various cyclic amines to furnish the final compounds 6a-h and 8a-h. Compounds were tested for their vasorelaxant activities against nor-adrenaline-induced spasm on thoracic rat aorta rings and compared to the reference drug, prazosin. Seven compounds showed higher activity than prazosin, especially compound 8d having an IC(50)=0.10 mM. Molecular modeling studies, including fitting of the synthesized compounds to a 3D-pharmacophore and their docking into optimized homology model as α(1)-AR antagonists showed high docking score and fit values. Most vasodilation activities of tested compounds are consistent with their molecular modeling results.
authors.affiliation: Pharmaceutical Chemistry department, Faculty of Pharmacy, Cairo University, 11562 Cairo, Egypt. fadi_mae@hotmail.com
authors.forename: Fadi M
authors.initials: FM
authors.lastname: Awadallah
authors.forename: Wafaa I
authors.initials: WI
authors.lastname: el-Eraky
authors.forename: Dalia O
authors.initials: DO
authors.lastname: Saleh
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D010793:Phthalazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D010793:Phthalazines; C043388:phthalazine