Tetrazole function, activity

N-Oxide Azaheterocycle Azole Pyrazole Imidazole Triazole Tetrazole N-Oxidation Cyclization Functionalization Activation Regioselectivity One pot... 

Among 24 compounds containing the tetrazole function prepared by Holland and Pereira [70], 5-(3-pyridyl)-tetrazole (XIII) was found to depress plasma-free fatty acid levels in the fasted dog most effectively. The hypoHpidemic activity of XIII was comparable to that of nicptinic and 3-pyridyl-acetic acids. In fact, the duration of activity was approximately 5 hours which is three times longer than that of nicotinic acid. Moreover, no rebound effect was observed after the hypoHpidemic activity of XIII, while the short inhibitory action of nicotinic acid was followed by a rise of plasma-free fatty acid concentration above the control level in the fasted dog. In contrast, compound XIII was found to be about 3,000 times less potent than nicotinic acid in the in vitro test in which the inhibition of norepinephrine-induced free fatty acid release from isolated adipose tissue was measured. In this assay, 3-pyridyl-acetic acid (IV) was approximately 600 times less active than nicotinic acid. PicoHnic acid and isonicotinic acid were even less active. The metaboHtes of nicotinic acid in man, namely, nicotinic acid amide, iV -methylnicotinamide and nicotinuric acid, were found to be about 10,000 times less active as Hpolysis inhibitors than nicotinic acid. Based on these findings, 5-(3-pyridyl)-tetrazole... 

ZD-9331 is a non-nucleosidic inhibitor of thymidylate synthase. It is also an antifolate, in which the quinazoline moiety replaces the pteridine entity, structurally close to methylene tetrahydrofolate (i.e., the second substrate of thymidylate synthase). Moreover, replacement of the acid function of glutamic acid by a tetrazole renders polyglutamination impossible. Consequently, ZD-9331 is active on tumors that are resistant to the usual antifolates. ... 

Compounds of type 106 are readily available by intramolecular dehydrogenation of appropriate triazenopyrazoles 105 (Scheme 61) <1987CB1375>. A general approach to the fused tetrazole system is provided via intermolecular [3 + 2] cycloadditions of the azide group with the activated nitrile functionality present in cyanamides, thiocyanates, and cyanates as illustrated in Schemes 6264 . 

A somewhat different but mechanistically related reaction is the [2 -f 3] cycloaddition of a functionalized alkyne or nitrile to an azide to form a disubstituted triazole (120) or tetrazole ring (121, 122), linking the respective functionalities irreversibly (Scheme 14b). This click chemistry was used by Sharpless and co-workers (120) in 2001 as a tool to probe biochemical catalysis and substrate activation. The ease of the Cu(I)-catalyzed reaction has created a true explosion (120-160) of simple coupling-functionalization chemistry of all types of biochemical components (sugars, DNA, proteins, enzymes, substrates, inhibitors) (131, 135, 136, 139, 142, 155, 157-160), polymers (126, 134, 140, 147, 154),... 

In further SAR study for C-3 heterocycle-substituted derivatives of squalestatins 1 and 3 [61], the inhibitory activities of squalestatin 3 analogs showed a greater dependence on the nature of the C-3 substituent, which is different from those of squalestatin 1 analogues. Potent squalene synthase inhibitory activities equivalent to those of squalestatins 1 and 3 were retained in C-3 analogues substituted with a tetrazol-5-yl functionality which closely mimics the parent carboxylic acid (see Table 1). Also, electrostatic potential maps studies showed that squalene synthase inhibitory activity similar to that of the methyl ester (IC50 = 220 nM) was retained only in those C-3 heterocycle-substituted squalestatin 3 analogues for which electrostatic potential maps of the C-3 substituent were closely similar to that of a methyl ester [61]. Squalene synthase inhibitory activities of several analogues substituted with a heterocyclic moiety at C-3 are shown in Table 1. 

The carboxylic function of active compounds has been changed to direct derivatives such as hydroxamic acids R— CO—NH—OH, acyl-cyanamides R—CO—NH—CN and acyl-sulfonamides R—CO—NH—SO2—R to planar acidic heterocycles such as tetrazoles, hydroxy-isoxazoles, etc., or even to non-planar sulfur- or phosphorus-derived acidic functions (Table 13.8). 

Activation of a nitrile with an electrophile other than an acid or Lewis acid has also shown applicability for entry into a 1,5-disubstituted tetrazole. A bromonium ion generated from an alkene 66 proved electrophilic enough to trap a nitrile which when treated with an azide source (TMSN3) provided the bromo-alkyl tetrazole 69. A broad range of alkenyl substrates and nitriles were shown to provide fair to excellent yield of the tetrazole. Of course, this method is limited in that nucleophilic functionality cannot be present or it will likely react. Considering the substituents of the products generated, it would be difficult to cleanly provide these intermediates via direct nucleophilic addition to the tetrazole. 

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