Exploration of 6,7-dimethoxyquinazoline derivatives as dual acting alpha(1)-and AT(1)-receptor antagonists: synthesis, evaluation, pharmacophore & 3D-QSAR modeling and receptor docking studies

The 6,7-dimethoxyquinazoline scaffold was further explored to provide dual acting alpha(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 alpha(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 alpha(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 (pA(2) for alpha(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 alpha(1)-antagonists and equipotent to losartan as AT(1)-antagonists in the in vivo animal model.