Synthesis of Tetrazole Regioisomers of Biphenyl as ACE Inhibitors

Abstract

Abstract. Novel angiotensin converting enzyme (ACE) inhibitors were designed based on the structure of commercially available sartans and synthesized by N-alkylation of 5-substituted-1H-tetrazole with 4'-(bromomethyl)-biphenyl-2-carbonitrile gave 1,5-and 2,5-regioisomers of tetrazole. The nitrile group appended to biphenyl nucleus was converted into tetrazole and later the tetrazole was ring transformed into 1,3,4-oxadiazole. The synthesized compounds were screened for the ACE inhibition and some of the compounds exhibited significant results.Keywords: Biphenyl, tetrazole, N-alkylation, regioisomers, 1,3,4-Oxadiazole, ring transformation, ACE inhibition IntroductionAll the cardiovascular diseases in the present era are caused mainly by "lifestyle disorder", a term coined to redefine hypertension. Although the causes of cardiovascular disease are many, hypertension stands to be the crucial one. A recent study suggests that hypertensive patients are more prone to develop type II diabetes [1]. Thus, these chronic diseases coexist, with increasing risk of coronary artery disease, kidney damage, vision problems, enlarging of heart, stroke and heart failure. Many drugs have been developed to treat such chronic diseases with reduced risk of side effects. Thus, the efficacy of hypertensive medications involves many etiologies and disease mechanisms to treat the hypertensive related chronic disease [2]. The first line therapy for the treatment of hypertension is angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers. The biphenyl-tetrazole is the key substrate [3][4][5], which belongs to a group of angiotensin II-receptor antagonists generally referred to as "sartans". These include Losartan, Valsartan and Candesartan which are useful in the treatment of hypertension, heart diseases, and bladder diseases and work by blocking the action of angiotensin II on its receptor ( Figure 1). Tetrazole is a heterocyclic moiety that functions as a carboxylic acid bioisostere with greater metabolic stability. It forms two hydrogen bonds with peptide residues in a biological target site which facilitates the binding interaction [6]. The negative charge of the tetrazolic anion is delocalized over all four nitrogens which play a major role in the clog P value and thus resulting in better oral bioavailability and cell penetration. It also exhibits many biological activities like antihypertensive [7,8], anti-inflammatory [9], endocannabinoid metabolism inhibitor, antibiotic [10] and anticonvulsant [11]. 1,3,4-Oxadiazole is a biologically active nucleus which shows a broad spectrum of pharmacological activities such as antimicrobial [12], antiprotozoal [13], anti-inflammatory [14], anti-tubercular [15] etc. Thus, the combination of two biological active moieties enhances the biological activities of the novel template.Considering all the above observations, we intended to synthesize novel scaffolds by N-alkylation of 5-substituted-1H-tetrazole 2a-d with 4'-(bromomethyl)-biphenyl-2-carbonitrile 1, there by aff...

Design and Synthesis of Angiotensin Converting Enzyme (ACE) Inhibitors: Analysis of the Role of Tetrazole Ring Appended to Biphenyl Moiety

“…These are useful in the treatment of hypertension. Majority of these sartans contain biphenyl‐tetrazole moiety as a common pharmacophore, which is appended to a heterocyclic group via a methylene group [25] . Structure Activity Relationship (SAR) studies of antihypertensive drugs revealed the requirement of following structural features to exhibit the potential activity.…”

Pyrido[1,2‐a]pyrimidin‐4‐ones: Ligand‐based Design, Synthesis, and Evaluation as an Anti‐inflammatory Agent

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