Exploration of 6,7-dimethoxyquinazoline derivatives as dual acting α- and AT-receptor antagonists: synthesis, evaluation, pharmacophore & 3D-QSAR modeling and receptor docking studies

The 6,7-dimethoxyquinazoline scaffold was further explored to provide dual acting α 1 - and AT 1 -receptor antagonists by synthesizing a series of derivatives and biologically evaluating the newly synthesized compounds. Based on the biological data of the current compounds and the earlier reported compounds, pharmacophore models were developed for α 1 - and AT 1 -receptor antagonist activities. Subsequently, 3D-QSAR models were also derived for antagonism for both the receptors. The developed 3D-QSAR models were validated using various statistical parameters and both the developed models were further validated using terazosin and prazosin as external compounds. Docking studies confirmed receptor-ligand stabilizing interactions of the balanced-dual active antagonist ( 110 ) in the active sites of both α 1 - as well as AT 1 -receptors, the structures of which were obtained by homology modeling. Two ( 42 and 110 ) of the compounds from the newly synthesized derivatives offered the highest potency ( p A 2 for α 1 = 9.45 and 8.77 and AT 1 = 8.36 and 8.60 respectively) with balanced modulation of both the receptors. Both the compounds were found to be slightly less potent to terazosin as α 1 -antagonists and equipotent to losartan as AT 1 -antagonists in the in vivo animal model. The 6,7-dimethoxyquinazoline scaffold was further explored to provide dual acting α 1 - and AT 1 -receptor antagonists by synthesizing a series of derivatives and biologically evaluating the newly synthesized compounds.