Synthesis and QSAR studies on hypotensive 1-[3-(4-substituted phenylthio) propyl]-4-(substituted phenyl) piperazines q Anil K. Saxena, a, * Jyoti Rao, a Ruchika Chakrabarty, a Mridula Saxena a and R. C. Srimal b a Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226001, India b Division of Pharmacology, Central Drug Research Institute, Lucknow 226001, India Received 18 September 2006; revised 11 December 2006; accepted 21 December 2006 Available online 23 December 2006 Abstract—A series of 1-[3-(4-substituted phenylthio) propyl]-4-(substituted phenyl) piperazines has been synthesized and evaluated for hypotensive activity. The QSAR studies indicate that resonance and hydrophobic parameters of the aryl substituents are impor- tant for hypotensive activity. The similar role of resonance parameter in describing the variance of 5-HT 2A receptor binding affinities of these compounds suggests a possible role of 5-HT 2A receptors in mediating the hypotensive action of title compounds. Ó 2006 Elsevier Ltd. All rights reserved. Hypertension is a state of abnormally high pressure in the arteries all the time. Between 85% and 90% of people suffer from primary hypertension (with no known cause), rest 10–15% of people have secondary hyperten- sion (caused by renal, endocrine or pregnancy related diseases). The disease is usually symptom less but if untreated, it may result in heart enlargement and failure, renal dysfunction and cerebrovascular accidents. Body mechanisms that control blood pressure are con- trolled by the sympathetic division of the autonomic ner- vous system and the kidneys. Drugs used, alone or in combination, for treatment of hypertension are diuretics, adrenergic blockers, centrally acting alpha-agonists, angiotensin-converting enzyme (ACE) inhibitors, angio- tensin II blockers, calcium channel blockers, direct vaso- dilators and more recently 5-HT antagonists. 1 One of the important vascular effects of 5-HT is its ability to act as a vasoconstrictor. The 5-HT 2A , 5-HT 2B and 5-HT 1B recep- tors have been implicated as mediators of 5-HT-induced contraction in vascular smooth muscle. 5-HT 2A recep- tors mediate contraction in many arteries including the rat thoracic aorta 2 and pulmonary arteries 3 . In our earli- er work, 1-(aryloxy/thioaryloxy)-3-(N-arylpiperazinyl) propanes and propanols, 4–9 series of 1-[3-(4-substituted phenylthio) propyl]-4-(substituted phenyl) piperazines and related compounds 10–12 including 1-(aryl-pipera- zin-1-yl)-1-oxo-2-(thioaryloxy/aryloxy) propanes 13 have been investigated for their hypotensive activity. Among these compounds 1-[3-(4-acetamidophenylthio) propyl]- 4-[3-methyl phenyl] piperazine 11 emerged as a potential antihypertensive agent. It showed activity comparable to centhaquin. 14 The QSAR studies on a set of the ana- logues of 1-[3-(4-acetamidophenylthio) propyl]-4-[3- methyl phenyl] piperazine indicated that the variance in activity is explained by the resonance and the hydropho- bicity effects of the substituents on the phenyl rings. Based on the above observations and in order to further explore the effect of aromatic substitution on hypoten- sive activity, another series of 1-[3-(4-substituted phenyl- thio) propyl]-4-(substituted phenyl) piperazines was synthesized and evaluated for their hypotensive activity in vivo. In order to study the possible role of 5-HT 2A receptor affinity in the observed hypotensive activity in these molecules, some selected compounds including the least and most active ones were evaluated for their affinities to 5-HT 2A receptors. The quantitative struc- ture–activity relationship (QSAR) studies have been car- ried out to analyze the observed variance in hypotensive activity in terms of the effect of physicochemical param- eters (hydrophobic, steric and electronic) where the reso- nance and hydrophobic parameters for the substituents in the thioaryloxy and arylpiperazine part, respectively, were found to be important for explaining the variance in hypotensive activity and the former in 5-HT 2A recep- tor binding affinity. These studies are reported in this paper. 0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2006.12.072 Keywords: Thioarylalkylpiperazines; Hypotensive; QSAR; 5-HT2A binding affinity; Hydrophobicity; Resonance. q CDRI Communication No. 7077. * Corresponding author. Tel.: +91 522 2612411 18; fax: +91 522 2623405; e-mail: anilsak@gmail.com Bioorganic & Medicinal Chemistry Letters 17 (2007) 1708–1712