Click chemistry inspired facile one-pot synthesis of mannosyl triazoles and their hemagglutination inhibitory properties: The effect of alkyl chain spacer length between the triazole and phthalimide moieties in the aglycone backbone.

An efficient one-pot synthesis of a new series of mannosyl triazoles has been achieved through CuAAC reaction where the alkyl chain spacer between the phthalimide moiety and the triazole ring in the aglycone backbone is varied from one methylene to six methylene units. The target compounds were evaluated in terms of their inhibitory potency against FimH using hemagglutination inhibition (HAI) assay. It was found that the length of four methylene units was the optimum for the fitting/binding of the compound to FimH as exemplified by compound 11 (HAI = 1.9 µM), which was approximately 200 times more potent than the reference ligand 1(HAI = 385 µM). The successful implementation of one-pot protocol with building blocks 1-7 and the architecture of ligand 11 will be the subject of our future work for developing more potent FimH inhibitors.

Synthesis and hemagglutination inhibitory properties of mannose-tipped ligands: The effect of terminal phenyl groups and the linker between the mannose residue and the triazole moiety.

Two families (A, B) of triazole conjugates derived from d-mannose possessing reversed linkage functionality were easily assembled by Cu(I) catalyzed azide-alkyne cycloaddition reaction (CuAAC). The mannose precursors were built with either 3-azidopropyl or propargyl aglycones whereas the phenyl moieties were built with terminal azide or propargyl groups, respectively. In a hemagglutination inhibition (HAI) assay, family A (7a-11a), where the linker between the mannose residue and the triazole ring is three carbons displayed a 3-5 fold enhancement in activity compared to family B (13a-17a) having methyl-triazolyl moiety. The representative ligand 7a, where the terminal phenyl ring is substituted with an ester group and Cl atom exhibited the highest inhibitory activity with an HAI titer of 8 µM. This compound could be a good candidate for the further design of potent mannosyl ligands targeting FimH fimbrial lectin.

2-Propynyl 2,3,4,6-tetra-O-acetyl-α-D-mannopyranoside.

The 2-propynyl group in the title compound, C(17)H(22)O(10), adopts an exoanomeric conformation, with the acetylenic group gauche with respect to position C1. Comparison of (13)C NMR chemical shifts from solution and the solid state suggest that the acetylenic group also adopts a conformation anti to C1 in solution. The pyranose ring adopts a (4)C(1) conformation. Of the three secondary O-acetyl groups, that on position O4, flanked by two equatorial groups, adopts a syn conformation, in agreement with recent generalizations [González-Outeiriño, Nasser & Anderson (2005). J. Org. Chem. 70, 2486-2493]. The acetyl group on position O3 adopts a gauche conformation, also in agreement with the recent generalizations, but that on position O2 adopts a syn conformation, not in agreement with the recent generalizations.

α-d-Mannoside ligands with a valency ranging from one to three: Synthesis and hemagglutination inhibitory properties.

Six mono-, di-, and trivalent α-d-mannopyranosyl conjugates built on aromatic scaffolds were synthesized in excellent yields by Cu(I) catalyzed azide-alkyne cycloaddition reaction (CuAAC). These conjugates were designed to have unique, flexible tails that combine a mid-tail triazole ring, to interact with the tyrosine gate, with a terminal phenyl group armed with benzylic hydroxyl groups to avoid solubility problems as well as to provide options to connect to other supports. Biological evaluation of the prepared conjugates in hemagglutination inhibition (HAI) assay revealed that potency increases with valency and the trivalent ligand 6d (HAI = 0.005 mM) is approximately sevenfold better than the best meta-oriented monovalent analogues 2d and 4d (HAI ≈ 0.033 mM) and so may serve as a good starting point to find new lead ligands.

Assembly and inhibitory activity of monovalent mannosides terminated with aromatic methyl esters: The effect of naphthyl groups.

A series of monovalent α-D-mannoside ligands terminated with aromatic methyl esters have been synthesized in excellent yields using the Cu(I) catalyzed azide-alkyne 1,3-dipolar cycloaddition ("click chemistry"). These mannosides were designed to have a unique aglycone moiety (tail) that combines a triazole ring attached to aromatic methyl esters via a six carbon alkyl chain. The mannose unit of these ligands was linked at the ortho, meta, and para positions of substituted methyl benzoates and 1-, 3-, and 6-substituted methyl 2-napthaoates. In hemagglutination assays, ligands (32A-38A) showed better inhibitory activities than the standard inhibitor, methyl α-D-mannopyranoside. Overall, the naphthyl-based mannoside ligand (37A) showed the best activity and therefore merits further development.

Unique tetrameric and hexameric mannoside clusters prepared by click chemistry.

The synthesis of novel tetrameric and hexameric mannoside clusters bearing 1,2,3-trizole linkages via Cu(I)-catalyzed azide-alkyne cycloaddition reaction ("click chemistry") is described. An attractive feature of these multiarmed mannoside clusters as potential inhibitors of uropathogenic Escherichia coli is the use of an aglycone whose length is designed to fit in the tyrosine gate. The acetylated mannosides were deprotected and the corresponding de-O-acetylated mannosides were found to exhibit good water solubility.

Syntheses of monohydroxy benzyl ethers of polyols: tri-O-benzylpentaerythritol and other highly benzylated derivatives of symmetrical polyols.

Symmetrical polyols can be converted into benzyl ethers with one free hydroxyl group in good yield by reaction of the monodibutylstannylene acetal with excess benzyl bromide in the presence of tetrabutylammonium bromide and diisopropylethylamine in xylene. The reaction pathway involves initial benzylation of the dibutylstannylene acetal to give benzyl and bromodibutylstannyl ethers; if a hydroxyl group remains unsubstituted, the latter ether ring closes and reacts further.

Synthesis of a nonavalent mannoside glycodendrimer based on pentaerythritol.

A nonavalent glycodendrimer bearing terminal alpha-d-mannopyranoside units has been synthesized with a convergent approach. Terminal trivalent mannoside dendrons bearing p-halophenyl ethers were prepared by glycosylation of pentaerythritol derivatives having three 2-hydroxyethyl ether substituents. Two efficient routes were developed for the synthesis of the pentaerythritol-based core (17), which has three terminal propargyl ethers. Conditions were found under which the triple Sonogashira coupling reaction of the dendron and the tri-O-propargyl ether (17) proceeded efficiently. The product was deprotected and it and precursors were fully characterized by NMR spectroscopy and FT-ICR mass spectrometry.