期刊
RSC ADVANCES
卷 6, 期 36, 页码 30661-30682出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/c6ra00589f
关键词
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资金
- UGC, New Delhi for the award of 'UGC-BSR One time research grant' [F.19-147/2015(BSR)]
- UGC-BSR-RFMS fellowship
- UGC project [41-716/2012-SR]
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.
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