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 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.