Design and synthesis of 6,7-dimethoxyquinazoline analogs as multi- targeted ligands for a 1 - and AII-receptors antagonism M. R. Yadav ⇑ , P. P. Naik, H. P. Gandhi, B. S. Chauhan, R. Giridhar Pharmacy Department, Faculty of Tech. & Engg., The M.S. University of Baroda, Vadodara 390001, Gujarat, India article info Article history: Received 14 December 2012 Revised 1 April 2013 Accepted 19 April 2013 Available online 30 April 2013 Keywords: Multiple-targeted ligands Quinazoline Dual inhibition Prazosin Losartan Hypertension abstract 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 dis- orders like diabetes, hypertension and hypercholesterolemia. After scrutinizing the SAR of prazosin-type a 1 -blockers and AII-antagonists it was planned to develop dual a 1 - and AII-antagonists. Five series of qui- nazoline derivatives were synthesized and evaluated as dual a 1 - and AII-antagonists on rat aortic strips for the blockade of known a 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 a 1 - as well as AII-receptor antagonists. Ó 2013 Elsevier Ltd. All rights reserved. It is increasingly being recognized that a balanced modulation of multiple targets can provide a superior therapeutic efficiency in comparison to targeting a single enzyme/receptor in a diseased state. 1 There is no single drug treatment of hypertension due to dif- ferences in etiology, risk factors and body constitution of individu- als. 2 It requires a combination therapy as a single drug of any class of antihypertensives proves ineffective. 3,4 The conventional treat- ment of hypertension involves combination of drugs from such categories of drugs as diuretics, a 1 -adrenergic receptor antago- nists, b-blockers, calcium channel blockers, ACE inhibitors, AII- receptor antagonists etc. Compared to drug combinations, there are certain advantages associated with a multiple-targeted ligand as a therapeutic agent, such as more predictable pharmacokinetic and pharmacodynamic relationship and improved patient compliance as a consequence of administration of a single drug at a time. It is interesting to note that of the known multiple targeted (multi-action) drugs only a few have been designed to act on the intended targets. Rest others have been serendipitously discovered wherein the modes of action of the drugs were elucidated retrospectively to be multiple tar- geted. Increase in the number of publications on the designing and development of multiple targeted molecules in recent times is an indication of developing interest in the field. 5–7 Rational designing approaches, in which structural features of selected ligands are combined into one single entity, have produced new ligands that act on a variety of targets. A key challenge in the designing of such multiple-targeted ligands is attaining a balanced activity at each target of interest while achieving a higher selectiv- ity and a suitable pharmacokinetic profile simultaneously. 8 The so called dual acting drugs (dimeric ligands) are designed by joining together the pharmacophores by a cleavable/noncleavable linker or more commonly by overlapping the pharmacophores of two drugs into a single chemical entity by taking advantage of common structural features of two or more classes of drugs. To integrate the pharmacophores of two drugs common structural features of both of the drugs are overlapped. There are numerous examples of hybrid molecules wherein dual bioactivities have been packed into a single chemical entity. Glitazones (insulin sensitizers) and fibrates (lipid lowering agents) act through PPARc and PPARa receptors respectively. The arylox- azole (1) is a combination of thiazolidinedione derivative (2) and fenofibric acid 9 (3). A dual acting hybrid sulphonamide (4) was ob- tained by linking propranolol, a b-blocker with mefruside, a diure- tic. 10 In prizidilol (5), hydralazine a well known vasodilator was integrated with a pharmacophoric group responsible for b-block- ing activity to afford a dual acting drug. 11 0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmcl.2013.04.054 ⇑ Corresponding author. Tel.: +91 265 2434187; fax: +91 265 2418927. E-mail address: mryadav11@yahoo.co.in (M.R. Yadav). Bioorganic & Medicinal Chemistry Letters 23 (2013) 3959–3966 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl