Synthesis, vasorelaxant activity, and molecular modeling study of some new phthalazine derivatives

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 IC50 = 0.10 mM. Molecular modeling studies, including fitting of the synthesized compounds to a 3D-pharmacophore and their docking into optimized homology model as α1-AR antagonists showed high docking score and fit values. Most vasodilation activities of tested compounds are consistent with their molecular modeling results.

Phthalazine derivatives were designed and tested for their vasorelaxant activities. Compound 8d had an IC50 = 0.10 mM. Molecular modeling, including 3D-pharmacophore and homology model as α1-AR antagonists was performed.Figure optionsDownload as PowerPoint slideHighlights
► New phthalazine derivatives were prepared as potential vasodilators.
► Vasorelaxant activity was evaluated using thoracic rat aorta rings.
► Compound 8d having an IC50 = 0.10 mM is more potent than the standard prazosin.
► 3D-pharmacophore and a homology model of α1-AR were conducted.