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University of Groningen Novel Applications of Tetrazoles Derived University of Groningen Novel Applications of Tetrazoles Derived from the TMSN3-Ugi Reaction Zhao, Ting IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2016 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Zhao, T. (2016). Novel Applications of Tetrazoles Derived from the TMSN3-Ugi Reaction. Rijksuniversiteit Groningen. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license. More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne- amendment. Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 01-10-2021 Chapter 2 Review: tetrazoles via multicomponent reaction routes Ting Zhao, Alexander Dömling, In preparation. Chapter 2 2.1 Introduction Tetrazoles are a class of doubly unsaturated five-membered ring aromatic heterocycles, containing one carbon and four nitrogen atoms (Scheme 2.1). They do not exist in nature. The first tetrazole derivative was obtained occasionally by the Swedish chemist J. A. Bladin in 1885.1 He proposed the name “tetrazole" for this new ring structure. Base on the number of the substitution, the systems can be classified into un-, mono- and disubstituted tetrazoles. Scheme 2.1. Tautomerism of tetrazole derivatives. Tetrazoles consist of the highest nitrogen contents among the stable heterocycles. They have wide applications in numerous fields, such as organic chemistry, coordination chemistry, the photographic industry, explosives, and in particular, medicinal chemistry. For example, tetrazole derivatives are investigated as potential explosives and also as rocket propellant formulations based on its high-energy properties.2 Meanwhile, the nitrogen atom-rich feature could be an environmentally benign component of gas generators with a high burn rate and relative stability.3 However, the most important and fruitful applications of tetrazoles are the utilization in medicinal chemistry. Apparently, the number of publications on new drugs and promising biologically active compounds containing the tetrazole moieties increases annually. To date, Drug Bank mentioned 43 FDA approved drugs that contain 1H- or 2H-tetrazole substituents; these compounds possess hypertensive, antimicrobial, antiviral, antiallergic, cytostatic, nootropic, and other biological activities (Table 2.1). Table 2.1. FDA approved drugs containing tetrazole moiety Valsartan Cefotiam Cefmenoxime Cefmetazole DB00177 DB00229 DB00267 DB00274 A broad spectrum of An antibiotic with a broad activity against both gram- spectrum of activity against Page | 10 Review: tetrazoles via multicomponent reaction routes Angiotensin- positive and gram-negative A third-generation both gram-positive and gram- receptor blocker microorganisms cephalosporin negative microorganisms antibiotic Olmesartan Cefpiramide Losatan Candesartan DB00275 DB00430 DB00678 DB00796 Antihypertensive A third-generation An angiotensin- An angiotensin-receptor agent, which cephalosporin antibiotic receptor blocker blocker (ARB) that may be belongs to the class (ARB) that may be used alone or with other of medications used alone or with agents to treat hypertension called angiotensin II other agents to treat receptor hypertension Alfentanil Pemirolast Ceforanide Irbesartan DB00802 DB00885 DB00923 DB1029 A short-acting A mast cell stabilizer that A second-generation An angiotensin receptor opioid anesthetic acts as antiallergic agent parenteral blocker (ARB) used mainly and analgesic of cephalosporin for the treatment of fentanyl antibiotic hypertension Cilostazol Cefamandole Cefazolin Forasartan DB01166 DB01326 DB01327 DB01342 A medication used A broad-spectrum A broad-spectrum A specific angiotensin II in the alleviation of cephalosporin antibiotic antibiotic antagonist, is used alone or the symptom of with other antihypertensive intermittent agents to treat hypertension claudication in individuals with peripheral vascular disease Cefonicid Cefoperazone Cefotetan Tasosartan DB01328 DB01329 DB01330 DB01349 Page | 11 Chapter 2 A second- Semisynthetic broad- A semisynthetic A long-acting angiotensin II generation spectrum cephalosporin cephamycin antibiotic (AngII) receptor blocker cephalosporin with a tetrazolyl moiety that is administered administered intravenously or intravenously or intramuscularly intramuscularly Pranlukast 2-(2f-Benzothiazolyl)-5- (5r,6s,7s,8s)-5- Nojirimycine Tetrazole DB01411 Styryl-3-(4f- Hydroxymethyl- DB02471 Phthalhydrazidyl)Tetrazoliu 6,7,8-Trihydroxy- A cysteinyl m Chloride Tetrazolo[1,5- leukotriene a]Piperidine receptor-1 DB01897 antagonist to DB02294 antagonize or reduce bronchospasm caused Mercaptocarboxylate 1-(5-Chloroindol-3-Yl)-3- N,N-Bis(4- 7-((Carboxy(4- Inhibitor Hydroxy-3-(2h-Tetrazol- Chlorobenzyl)-1h- Hydroxyphenyl)Acetyl)Amin DB02706 5-Yl)-Propenone 1,2,3,4-Tetraazol-5- o)-7-Methoxy-(3-((1-Methyl- DB03118 Amine 1h-Tetrazol-5- DB04037 Yl)Thio)Methyl)-8-Oxo-5- Oxa-1-Azabicyclo[4.2.0]Oct- 2-Ene-2-Carboxylic Acid DB04342 3-(4-Phenylamino- Latamoxef N-(1,4-Dihydro-5H- Phenylamino)-2- DB04570 tetrazol-5-ylidene)-9- (1h-Tetrazol-5-Yl)- oxo-9H-xanthene-2- Acrylonitrile Broad- spectrum beta- sulfonamide lactam antibiotic DB04430 DB04698 The successful insertion of tetrazoles used as components of materials for medicinal purposes is supported by the concept of bioisosterism which was initially defined by Friedman.4 Bioisosterism has been identified as one approach used by the medicinal chemist for the rational modification of lead compounds into safer and more clinically effective agents. And it also is classified as either classical or nonclassical. Carboxylic acid functional group is an important constituent of a pharmacophore. However, faced to the obvious drawbacks, including metabolic Page | 12 Review: tetrazoles via multicomponent reaction routes instability, toxicity and limited passive diffusion across biological membranes, medicinal chemists always investigate to employ carboxylic acid bioisosteres to avoid part of these disadvantages and meanwhile remain the desired attributes of the acid moiety. 1,5-Disubstituted tetrazoles are effective bioisosteres for cis-amide bonds in peptidomimetic, and 5-substituted tetrazoles are surrogates for carboxylic acids. The introduction of the tetrazole ring into a molecule of an organic substrate quite often leads not only to an increase in the efficacy but also to an increase in the prolongation of drug action. These improvements are all based on the structural features of tetrazole ring. First of all, both carboxylic acids and tetrazoles exhibit a planar structure. However, tetrazoles show both aliphatic and aromatic properties and have the similar pKa values with the corresponding carboxylic acids (4.5 – 4.9 vs 4.2 – 4.4, respectively). The ability to delocalize the negative charge tetrazoles over five atoms resulting in a reduced per atom charge could help to penetrate through biological membranes and be favorable for a receptor–ligand interaction, or may complicate the contact, depending on the local charge density available at the interface. Secondly, same like their carboxylic acid counterparts, tetrazoles are ionized at physiological pH (≈7.4), but are almost 10 times more lipophilic than the corresponding carboxylates which could facilitate further a drug molecule to pass through cell membranes. Thirdly, the high- density of nitrogens in tetrazoles could provide more opportunities to form hydrogen bonds with receptor recognition sites which explain the sometimes enhanced binding affinity. Last but not least, tetrazoles are resistant to many biological metabolic degradation pathways which are conjugation reactions to form β-N-glucuronides, a metabolic fate that often befalls aliphatic carboxylic acids to form o-β-glucuronic acid conjugates. Thus, effective and time-saving synthetic methods are important to build up libraries of tetrazoles for high-throughput screening and other low throughput pharmaceutical research. Multicomponent reactions (MCRs) are chemical reactions where more than two compounds react to form a single product in a sequence with several descriptive features, such as atom economy, efficiency and convergence. Ugi and co-worker, firstly reported the use of HN3 replacing carboxylic acid in the Passerini and Ugi reactions to form tetrazole derivatives in 1960s. And since then, numerous advancements were published on the synthesis of tetrazoles via multicomponent reaction. In this review, we summarize the currently mostly used synthetic routes for the preparation of tetrazole derivatives through non-multicomponent reaction. Our focus, however is on the use of multicomponent
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