Abstract1,5-Diarylsubstituted 1,2,3-triazoles are formed in high yield from aryl azides and terminal alkynes in DMSO in the presence of catalytic tetraalkyl ammonium hydroxide. The reaction is experimentally simple, does not require a transition-metal catalyst, and is not sensitive to atmospheric oxygen and moisture.The copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) is a reliable means for the synthesis of 1,4-disubstituted-1H-1,2,3-triazoles. 1 The exceptional stability of 1,2,3-triazoles and the availability of a reliable synthesis leading to these heterocycles have enabled widespread applications of this previously underutilized class of azoles in medicinal chemistry, chemical biology and materials science. 2 In contrast to the 1,4-disubstituted-1H-1,2,3-triazoles, general and regioselective routes leading to the 1,5-regioisomers are not as well developed. [3][4][5][6][7][8] Although syntheses relying on the nucleophilic attack by the acetylide at the electrophilic terminal nitrogen of the azide are known, 9 the requirement for the stoichiometric lithium or magnesium acetylide reagent imposes obvious limitations on the range of functional groups that are compatible with these processes. Reported here is a mild and experimentally simple catalytic method for the generation of the reactive acetylides which readily react with organic azides resulting in the exclusive formation of 1,5-disubstituted triazoles.We envisioned that the high acidity of aryl acetylenes in dimethylsulfoxide [10][11][12] should allow formation of the reactive acetylide species by treatment of the alkyne with a hydroxide or fokin@scripps.edu. Supporting Information Available. Experimental procedures, characterization data, copies of 1 H NMR and 13 C NMR spectra. This material is available free of charge on the Internet at http://pubs.acs.org. alkoxide base in this solvent. In fact, formation of acetylide intermediates has been proposed by Ishikawa and co-workers in their studies of the alkynylation of ketones. 13 Screening of various hydroxides and alkoxides confirmed this hypothesis, revealing that anhydrous sodium, potassium, cesium hydroxides, and aqueous tetramethylammonium and benzyltrimethylammonium hydroxides catalyze formation of 1,5-diarylsubstituted-1H-1,2,3-triazoles in DMSO at room temperature (Table 1). NIH Public AccessDry DMSO and less nucleophilic bases such as potassium tert-butoxide can also be used to minimize hydrolysis of substrates which contain base-sensitive functionalities. In many cases, the desired products precipitated upon addition of 5-20× volume of ice-cold water and were isolated by simple filtration. Reactions in DMSO afforded higher isolated yield than in DMF on larger scale and at higher concentration. Although tetraalkylammonium hydroxides resulted in the slightly diminished yield of the product compared to powdered KOH, the shorter reaction time and the experimental convenience of using aqueous base solutions make tetraalkylammonium hydroxides advantageous catalysts for practical reasons.While o...

Nicotinic acetylcholine receptors (nAChRs), being responsible for mediating key physiological functions, are ubiquitous in the central and peripheral nervous systems. As members of the Cys loop ligand-gated ion channel family, neuronal nA-ChRs are pentameric, composed of various permutations of α (α2 to α10) and β (β2 to β4) subunits forming functional heteromeric or homomeric receptors. Diversity in nAChR subunit composition complicates development of selective ligands for specific subtypes, since the five binding sites reside at the subunit interfaces. The acetylcholine binding protein (AChBP), a soluble extracellular domain homologue secreted by mollusks, serves as a general structural surrogate for the nAChRs. In this work, homomeric AChBPs from Lymnaea and Aplysia snails were used as in situ templates for the generation of novel and potent ligands that selectively bind to these proteins. The cycloaddition reaction between building block azides and alkynes to form stable 1,2,3-triazoles generated the leads. The extent of triazole formation on the AChBP template correlated with the affinity of the triazole product at the nicotinic ligand binding site. Instead of the in situ protein-templated azide-alkyne cycloaddition reaction occurring at a localized, sequestered enzyme active center as previously shown, we demonstrate that the in situ reaction can take place at subunit interfaces of an oligomeric protein and can thus be used as a tool for identification of novel candidate nAChR ligands. The crystal structure of one of the in situ formed triazole–AChBP complexes shows binding poses and molecular determinants of interactions predicted from structures of known agonists and antagonists. Hence, the click chemistry approach with an in situ template of a receptor provides a novel synthetic avenue for generating candidate agonists and antagonists for ligand-gated ion channels.

VIM-2 is an Ambler class B metallo-β-lactamase (MBL) capable of hydrolyzing a broad-spectrum of β-lactam antibiotics. Although the discovery and development of MBL inhibitors continues to be an area of active research, an array of potent, small molecule inhibitors has yet to be fully characterized for VIM-2. In the presented research, a compound library screening approach was used to identify and characterize VIM-2 inhibitors from a library of pharmacologically active compounds as well as a focused “click” chemistry library. The four most potent VIM-2 inhibitors resulting from a VIM-2 screen were characterized by kinetic studies in order to determine Ki and mechanism of enzyme inhibition. As a result, two previously described pharmacologic agents, mitoxantrone (1,4-Dihydroxy-5,8-bis([2-([2-hydroxyethyl]amino)ethyl]amino)-9,10-anthracenedione) and 4-chloromercuribenzoic acid (pCMB) were found to be active, the former as a non-competitive inhibitor (Ki = K′i = 1.5 ± 0.2 μM) and the latter as a slowly reversible or irreversible inhibitor. Additionally, two novel sulfonyl-triazole analogs from the click library were identified as potent, competitive VIM-2 inhibitors: N-((4-((but-3-ynyloxy)methyl)-1H-1,2,3-triazol-5-yl)methyl)-4-iodobenzenesulfonamide (1, Ki = 0.41 ± 0.03 μM) and 4-iodo-N-((4-(methoxymethyl)-1H-1,2,3-triazol-5-yl)methyl)benzenesulfonamide (2, Ki = 1.4 ± 0.10 μM). Mitoxantrone and pCMB were also found to potentiate imipenem efficacy in MIC and synergy assays employing E. coli. Taken together, all four compounds represent useful chemical probes to further investigate mechanisms of VIM-2 inhibition in biochemical and microbiology-based assays.

Metallo-ß-lactamases (MBL) are an emerging cause of bacterial resistance to antibiotic treatment. The VIM-2 ß-lactamase is the most commonly encountered MBL in clinical isolates worldwide. Described here are potent and selective small molecule inhibitors of VIM-2 containing the arylsulfonyl-NH-1,2,3-triazole chemotype that potentiate the efficacy of the ß-lactam, imipenem, in E. coli.

The acetylcholine-binding proteins (AChBPs), which serve as structural surrogates for the extracellular domain of nicotinic acetylcholine receptors (nAChRs), were used as reaction templates for in situ click-chemistry reactions to generate a congeneric series of triazoles from azide and alkyne building blocks. The catalysis of in situ azide-alkyne cycloaddition reactions at a dynamic subunit interface facilitated the synthesis of potentially selective compounds for nAChRs. We investigated compound sets generated in situ with soluble AChBP templates through pharmacological characterization with ␣7 and ␣4␤2 nAChRs and 5-hydroxytryptamine type 3A receptors. Analysis of activity differences between the triazole 1,5-synand 1,4-anti-isomers showed a preference for the 1,4-antitriazole regioisomers among nAChRs. To improve nAChR subtype selectivity, the highest-potency building block for ␣7 nAChRs, i.e., 3␣-azido-N-methylammonium tropane, was used for additional in situ reactions with a mutated Aplysia californica AChBP that was made to resemble the ligand-binding domain of the ␣7 nAChR. Fourteen of 50 possible triazole products were identified, and their corresponding tertiary analogs were synthesized. Pharmacological assays revealed that the mutated binding protein template provided enhanced selectivity of ligands through in situ reactions. Discrete trends in pharmacological profiles were evident, with most compounds emerging as ␣7 nAChR agonists and ␣4␤2 nAChR antagonists. Triazoles bearing quaternary tropanes and aromatic groups were most potent for ␣7 nAChRs. Pharmacological characterization of the in situ reaction products established that click-chemistry synthesis with surrogate receptor templates offered novel extensions of fragment-based drug design that were applicable to multisubunit ion channels.

We have succeeded in the synthesis of propargyl azides containing 1-or 3-phenylthio functionalities. The selective oxidation of their sulfur atoms to sulfoxides and sulfones allows access to the first propargyl azides bearing acceptor substituents. Interestingly, the prototropic rearrangement of the latter propargyl azides leads to the formation of allenyl azides with relatively high stabilities and with moderate to good yields. Propargyl azides containing phenylthio functionalities react in the presence of nucleophiles to afford the expected N-un-

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