Exploration of 6,7-dimethoxyquinazoline derivatives as dual acting α1- and AT1-receptor antagonists: synthesis, evaluation, pharmacophore & 3D-QSAR modeling and receptor docking studies

Abstract

The 6,7-dimethoxyquinazoline scaffold was further explored to provide dual acting α₁- and AT₁-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 α₁- and AT₁-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 α₁- as well as AT₁-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 (pA₂ for α₁ = 9.45 and 8.77 and AT₁ = 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 α₁-antagonists and equipotent to losartan as AT₁-antagonists in the in vivo animal model.