Library triazoles

More recently, Somfai and coworkers have reported on the efficient coupling of a set of carboxylic acids suitable as potential scaffolds for peptide synthesis to a polymer-bound hydrazide linker [24]. Indole-like scaffolds were selected for this small library synthesis as these structures are found in numerous natural products showing interesting activities. The best results were obtained using 2-(7-aza-l H-benzo-triazol-l-yl)-l,l,3,3-tetramethyluronium hexafluoride (HATU) and N,N-diisopropyl-ethylamine (DIEA) in N,N-dimethylformamide as a solvent. Heating the reaction mixtures at 180 °C for 10 min furnished the desired products in high yields (Scheme 7.4). In this application, no Fmoc protection of the indole nitrogen is required. 

The synthesis of 1,2,4-triazole-fimctionalized solid support 72 and its use in the solid-phase synthesis of various tiisubstituted 1,2,4-triazoles 73 was reported <990L1189>. A solid-phase library synthesis of triazolopyridazines 76 was achieved by [4+2] cycloaddition of diene amides 74 with 4-substituted urazines 75 <99TL619>. 

Solid-phase library synthesis of triazolopyridazines via a [4+2] cycloaddition strategy has been accomplished <99TL619>. Intramolecular bis-Mannich reaction of 3-aryl-5-mercapto-13,4-triazole, formaldehyde and a-phenylethylamine yields chiral 5-aryltriazolo[3,4-ft]-[133]thiadiazine derivatives. These compounds have been screened for antibacterial activities and some of them show potent biological activity <99SC2027>. 

Figure 7.18 Representative in situ Click chemistry reaction analysis by HPLC-SIM-MS the triazole product is indicated by the dashed line, (a) Triazole products obtained by conventional synthesis with Cu(l) catalysis, (b)-(d) Microfuidic device reactions performed at 37 °C for 40 h (b) in the presence of CA II, (c) in the presence ofCA II and potent CA inhibitor to block the CA active site and (d) in the absence of CA II. (e) Reaction performed at 37° C for 40 h in microtitre plate. Reproduced with permission from Wang,., Sui, C., Mocharla, V.P., Lin, R.J., Phelps, M.E., Kolb, H.C. and Tseng, H.-R., Integrated microfluidics for parallel screening of an in situ click chemistry library. Angewandte Chemie International Edition 2006, 45, 5276-5281. Copyright Wiley-VCH Verlag GmbH.

The fragment library consisted of tacrine and ethidium derivatives with tethers of variable lengths to both azides and alkynes (Figure 10.6). In total, the library included 36 different tacrine-ethidium combinations. Each combination could form two regioisomeric triazoles, so a grand total of 72 different products was possible. 

The regioselectivity of the reaction depends on electronic and steric effects and is somewhat predictable. For example, the addition of alkynes to azides, which is an interesting reaction for the generation of 1,2,3-triazole libraries by the simple reaction of two molecules leads to regioisomers ... 

Other isosteric replacements have also been attempted and have resulted in modest Icmt inhibitors, including secondary amines, phosphona-mides, carbamates, and triazoles (Jaimeen D. Majmudar, unpubhshed data). Secondary amines are the weakest inhibitors in this survey. The phosphona-mides and triazoles are in fact modest inhibitors, although not as potent as the SMFCs. In this library, the farnesyl hpid chain was held constant further fortifying the hypothesis that the enzyme-binding pocket is more tolerant to substitution when the key lipid recognition motif is present. 

Several unique heterocyclic fused-1,2,4-triazole structures have been published. Pyridine amination of 216 with O-mesitylenesulfonylhydroxylamine followed by condensation with various aryl and heterocyclic aldehydes and subsequent cyclization and oxidation gave triazolopyridines 217 <03TL1675>. Triazolopyridines 217 were utilized in the direct conversion to the triazolopyridine amides 218 with methylaluminoxane premixed with amines in a combinatorial library synthesis. A convenient synthesis of novel 4-(l,2,4-triazol-l-yl)-2-pyrazolines and their derivatives has been reported <03SC1449>. A novel triheterocyclic ring system, thieno[2,3-y][l,2,4]triazolo[l,5-a]azepines, has been published <03S1231>. 

The Cu -catalysed azide alkyne 1,3-dipolar cycloaddition (CuAAC) click chemistry has also been used to synthesize a library of a,/ -D-glucopyranosyl triazoles (iii). The synthesized triazoles proved to be potential glycosidase inhibitors [15]. 

A potent inhibitor against human a(l,3)-fucosyltransferase VI was identified from a GDP-triazole library of 85 compounds, which was produced by the Cu(I)-catalyzed [2 + 3] cycloaddition reaction between azide and acetylene, followed by in situ screening without product isolation (O Scheme 13) [155]. Kinetic evaluation of the purified inhibitor (O Scheme 13) showed that it is a competitive inhibitor against GDP-fucose with Ki = 62 nM, which would make this compound the first nanomolar and most potent inhibitor of Fuc-Ts. 

A library of glycoconjugate benzenesulfonamides that contain carbohydrate-triazole units has been evaluated for their ability to inhibit three human transmembrane carbonic anhy-drase isoz5mies hCA IX, hCA XII and hCA XIV which have potential as dmg targets OFig. 73 [118]. 

Wang s group constructed a coumarin library by using so-called click chemistry, which involves Cu(I)-catalyzed Husigen 1,3-dipolar cycloaddition of azides with alkynes to afford quantitative formation of a triazole ring under mild conditions.20 They prepared seven 3-azidocoumarin derivatives and one 4-azidocoumarin, each of which was reacted with 24 acetylenes (Fig. 18.5). 

Tornoe, C. W., Sanderson, S. J., Mottram, J. C., Coombs, G. H., and Meldal, M. (2004) Combinatorial library of peptidotriazoles Identification of [1,2,3]-triazole inhibitors against a recombinant Leishma-nia mexicana cysteine protease. J. Comb. Chem. 6, 312-324. 

Polystyrene-sulfonyl hydrazide resins 153 reacted with various amines to give regiospecifically 1,4-disubstituted-l,2,3-triazoles 154 via traceless cleavage reactions <04TL6129>. A library of peptidotriazoles were prepared by solid-phase peptide synthesis combined with a regiospecific copper(I)-catalyzed 1,3-dipolar cycloaddition between resin-bound alkynes and protected amino azides <04JCO312>. 

A parallel solid-phase synthesis of l,3,4-thiadiazolium-2-aminides involves trimethylsilyl chloride mediated cyclization of resin bound aldehydes 269 and 1,4,-disubstituted thiosemi-carbazides 268 <04JCO746>. Two additional combinatorial approaches have been developed to prepare focused libraries of 1,3,4-thiadiazoles <0478627 04BBR1053>. 1,3,4-Thiadiazoles 273 are prepared by condensation of triazole 271 with various carboxylic acids 272 in the presence of phosphorus oxychloride <04IJHC69>. 

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