Design and synthesis of 6,7-dimethoxyquinazoline analogs as multi-targeted ligands for α1- and AII-receptors antagonism

Multiple-targeted ligands can have certain advantages for the management of hypertension which has multiple controls. Molecules with dual bioactivities are available in literature for treating metabolic disorders like diabetes, hypertension and hypercholesterolemia. After scrutinizing the SAR of prazosin-type alpha(1)-blockers and AII-antagonists it was planned to develop dual alpha(1)- and AII-antagonists. Five series of quinazoline derivatives were synthesized and evaluated as dual alpha(1)- and AII-antagonists on rat aortic strips for the blockade of known alpha(1)- and AII-agonist mediated contractions. Many compounds showed balanced activity on both the receptors but compound (22) was found to be the most active derivative having higher antagonistic activity on both the receptors. In the in vivo experiments the chosen compound (22) was slightly less active than prazosin but was found to be equipotent to losartan. These findings shed a new light on the structural requirements for both alpha(1)- as well as AII-receptor antagonists. (c) 2013 Elsevier Ltd. All rights reserved.