Design, Synthesis and Pharmacological Screening of Novel Antihypertensive Agents Using Hybrid Approach Shashikant V. Bhandari * , Kailash G. Bothara, Ajit A. Patil, Trupti S. Chitre, Aniket P. Sarkate, Suraj T. Gore, Sudarshan C. Dangre, Chetan V. Khachane Dept. of Pharm. Chem. (PG wing), A.I.S.S.M.S. College of Pharmacy, Near RTO, Kennedy Road, Pune 411 001, Maharashtra, India article info Article history: Received 19 July 2008 Revised 11 October 2008 Accepted 14 October 2008 Available online 17 October 2008 Keywords: Hybrid Antiarrhythmic Antihypertensive Vasorelaxation NO donor abstract Eight derivatives of general formula 2-(2-(4-(3-((5-substituted methylene)-4-oxo-2-(phenylimino)thiaz- olidin-3-yl)-2-hydroxypropylamino)benzoyl)hydrazinyl)-2-oxoethyl nitrate were synthesized and tested for electrocardiographic, antiarrhythmic, vasorelaxing and antihypertensive activity as well as for in-vitro nitric oxide (NO) releasing ability. Compound 8b 2-(2-(4-(3-(5-benzyliden-4-oxo-2-(phenylimino)thiaz- olidin-3-yl)-2-hydroxypropylamino)benzoyl)hydrazinyl)-2-oxoethyl nitrate, was the most potent in this series. The pharmacological results suggested that the antiarrhythmic effects of these compounds were related to their adrenolytic properties which are believed to be due to the presence of the 5-(substi- tuted)methylen-2-(phenylimino)thiazolidin-4-one moiety with less bulky, electron donating substituent on the phenyl ring at 5th position of the thiazolidin-4-one. In conclusion, most of the synthesized com- pounds were significantly potent as antiarrhythmic and antihypertensive; this might be due to the pres- ence of different pharmacopores which might act at different locations with different mode of action. Further insights of the same can be obtained by doing investigation at receptor level. The potency of com- pounds 8a–8h were promising enough to continue further experiments. Ó 2008 Elsevier Ltd. All rights reserved. 1. Introduction Most of currently used antihypertensive agents can not be used as a single drug therapy because of several toxicities, side effects associated with these drugs. Multiple dose therapies make the re- gime complicated and less successful. One of the most important goals in organic and medicinal chemistry is the design and synthe- sis of molecules that have value as therapeutic agents. In this re- gard, heterocyclic compounds have proven to be versatile support structures that offer a high degree of structural diversity. 1 A problem often faced in the treatment of certain diseases is the complex and heterogeneous pathogenesis. A variety of mediators can be involved in the pathophysiological process leading to a dis- ease, in many instances; treatment with a single drug cannot ade- quately control the illness. Sometimes, the use of a therapeutic agent alone in the treatment of a disease may be limited by side ef- fects caused by its own action. Then combinations of drugs with different pharmaco-therapeutic effects are feasible. Combination drug therapy can be applied either to overcome the side effects of the single drug or to add beneficial effects. The principle of com- bination drug therapy can be achieved by either using concomitant administration of two or more single active drugs or by designing drugs in which more than one active pharmacophore are combined in one molecule, so called hybrid molecules. These hybrid mole- cules often consist of different pharmacophoric groups which are linked to each other via spacers. 2 In the long-term treatment of hypertension, there is no single antihypertensive drug which is able to normalize the elevated blood pressure in all hypertensive patients. b-Adrenoceptors are known to play an important role in the regulation of the autonomic nervous system and b-blockers have been shown to be useful in the pharmacotherapy of serious and widespread cardiovascular diseases. 3,4 Nitric oxide (NO) donors have been used for many years in the treatment of various clinical conditions, particularly coronary arte- rial diseases. 5 Though vasodilatation reduces blood pressure by directly relaxing peripheral vascular smooth muscles, the reduc- tion in blood pressure leads to a reflux increase in sympathetic tone, followed by increase in heart rate, cardiac output, and plasma rennin activity, which attenuate antihypertensive effect. It was reported that these undesirable effects of vasodilators could be eliminated by simultaneous treatment with b-blockers and the possible increase in peripheral vascular resistance induced by b-blockers was eliminated by concomitant use of vasodilators. In order to improve patient compliance, we have developed hybrid compounds containing three different pharmacophores viz. propa- nolamine possessing the characteristics of a typical b-antagonist, thiazolidinone component responsible antiarrythmic activity and of a ‘slow NO donor’, by adding NO-donor side chain. These new 0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2008.10.032 * Corresponding author. Tel.: +91 20 26058204; fax: +91 20 26058208. E-mail address: drugdesign1@gmail.com (S.V. Bhandari). Bioorganic & Medicinal Chemistry 17 (2009) 390–400 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc