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A novel and highly efficient copper-catalyzed tandem synthesis of triazoloquinazolinones is explored. The synthetic strategy involves a sequential one-pot click reaction followed by aerobic intramolecular C-H amidation. Two distinct and important transfor

In the present work, new benzimidazole linked 1,2,3-triazole hybrids have been synthesized and screened for antiproliferative and EGFR kinase inhibitory activities.The structures of these hybrids were elucidated using IR, NMR, mass spectrometry and elemen

We have obtained the X-ray crystal structure of the galectin-8 N-terminal domain (galectin-8N) with a previously reported quinoline–galactoside ligand at a resolution of 1.6 ?. Based on this X-ray structure, a collection of galactosides derivatised at O3 with triazole, benzimidazole, benzothiazole, and benzoxazole moieties were designed and synthesised. This led to the discovery of a 3-O-(N-methylbenzimidazolylmethyl)–galactoside with a Kd of 1.8 μM for galectin-8N, the most potent selective synthetic galectin-8N ligand to date. Molecular dynamics simulations showed that benzimidazole–galactoside derivatives bind the non-conserved amino acid Gln47, accounting for the higher selectivity for galectin-8N. Galectin-8 is a carbohydrate-binding protein that plays a key role in pathological lymphangiogenesis, modulation of the immune system, and autophagy. Thus, the benzimidazole-derivatised galactosides represent promising compounds for studies of the pathological implications of galectin-8, as well as a starting point for the development of anti-tumour and anti-inflammatory therapeutics targeting galectin-8.

Abstract: 2-Azidobenzoic acid has undergone rearrangement into 2-[(2-carboxyphenyl)amino]-6-formylnicotinic acid under irradiation in aqueous-organic media in the presence of acetates of alkali or alkaline earth metals. The structure of the resulting comp

A total of 15 new 4(3H)-quinazolinone derivatives containing a pyrazole carboxamide moiety were designed and synthesized in this study. The structures of the target compounds were elucidated using 1H NMR, 13C NMR, MS, and elemental a

A catalyst-controlled highly chemoselective and regioselective intramolecular cycloamidation of triazol-1-ylbenzamides toward the synthesis of scarcely known heterocycles is reported. In the presence of a palladium catalyst, this cycloisomerization reacti

Abstract: A novel series of 1,2,3-triazolo-benzodiazepine derivatives 6a–o has been synthesized and evaluated in vivo for their anticonvulsant activities using by pentylenetetrazole (PTZ)- and maximal electroshock (MES)-induced seizures in mice. The synth

An efficient four-step, six-transformation protocol was developed to afford bioactive N-alkyl- or N-arylamide (E)-arylamidines featuring strategic amidine C3 modifications which were inaccessible or low yielding by previous methods. This synthetic approac

The latency-associated nuclear antigen (LANA) is required for latent replication and persistence of Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8. It acts via replicating and tethering the virus episome to the host chromatin and exerts other functions. We conceived a new approach for the discovery of antiviral drugs to inhibit the interaction between LANA and the viral genome. We applied a biophysical screening cascade and identified the first LANA binders from small, structurally diverse compound libraries. Starting from a fragment-sized scaffold, we generated optimized hits via fragment growing using a dedicated fluorescence-polarization-based assay as the structure-activity-relationship driver. We improved compound potency to the double-digit micromolar range. Importantly, we qualified the resulting hit through orthogonal methods employing EMSA, STD-NMR, and MST methodologies. This optimized hit provides an ideal starting point for subsequent hit-to-lead campaigns providing evident target-binding, suitable ligand efficiencies, and favorable physicochemical properties.

The latency-associated nuclear antigen (LANA) is required for latent replication and persistence of Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8. It acts via replicating and tethering the virus episome to the host chromatin and exerts other functions. We conceived a new approach for the discovery of antiviral drugs to inhibit the interaction between LANA and the viral genome. We applied a biophysical screening cascade and identified the first LANA binders from small, structurally diverse compound libraries. Starting from a fragment-sized scaffold, we generated optimized hits via fragment growing using a dedicated fluorescence-polarization-based assay as the structure-activity-relationship driver. We improved compound potency to the double-digit micromolar range. Importantly, we qualified the resulting hit through orthogonal methods employing EMSA, STD-NMR, and MST methodologies. This optimized hit provides an ideal starting point for subsequent hit-to-lead campaigns providing evident target-binding, suitable ligand efficiencies, and favorable physicochemical properties.

New substituted 1-arylbenziodoxolones were prepared and their reactivity with azide anion as a nucleophile was investigated. It was found that independent of the presence of substituents, all reactions of 1-arylbenziodoxolones proceed as nucleophilic substitution of the iodonium leaving group in the electron-deficient benziodoxolone benzene ring. The presence of bulky substituents in the ortho position of the aryl ring slows the reaction down, while the presence of a moderately electron-withdrawing bromine substituent in para position to the iodine atom in the benziodoxolone ring moderately increases the rate of substitution. The presence of a strongly electron-withdrawing nitro group in the para position to the iodine atom in the benziodoxolone ring dramatically increases the rate of substitution. These observations are in agreement with the electronic requirements for internal nucleophilic substitution in the benziodoxole ring. A quantum-chemical computational study of the possible reaction paths is in agreement with the observed effects of substituents on the reactivity of arylbenziodoxolones in this reaction.

A rapid and elegant tandem azide–isocyanide cross-coupling/cyclization protocol has been developed based on a nitrene transfer reaction. The palladium-catalyzed ligand-free methodology led to the synthesis of three different heterocyclic scaffolds with excellent atom/step/redox economy. Studies based on first-principles-based quantum calculations and control experiments unraveled a concerted process of nitrene transfer reaction on isocyanides, ruling out the metallaaziridine intermediate reported earlier. This finding could pave the way for novel applications of nitrene transfer reactions to generate bioactive heterocycles. (Figure presented.).

A novel set of 64 analogues based on our lead compound 1 was designed and synthesized with an initial objective of understanding the structural requirements of ligands binding to a highly perplexing substrate-binding site of P-glycoprotein (P-gp) and their effect on modulating the ATPase function of the efflux pump. Compound 1, a stimulator of P-gp ATPase activity, was transformed to ATPase inhibitory compounds 39, 53, and 109. The ATPase inhibition by these compounds was predominantly contributed by the presence of a cyclohexyl group in lieu of the 2-aminobenzophenone moiety of 1. The 4,4-difluorocyclohexyl analogues, 53 and 109, inhibited the photolabeling by [125I]-IAAP, with IC50 values of 0.1 and 0.76 μM, respectively. Selected compounds were shown to reverse paclitaxel resistance in HEK293 cells overexpressing P-gp and were selective toward P-gp over CYP3A4. Induced-fit docking highlighted a plausible binding pattern of inhibitory compounds in the putative-binding pocket of P-gp. The current study underscores the stringent requirement by P-gp to bind to chemically similar molecules.

Several classes of ligands for Protease-Activated Receptors (PARs) have shown impressive anti-inflammatory and cytoprotective activities, including PAR2 antagonists and the PAR1-targeting parmodulins. In order to support medicinal chemistry studies with hundreds of compounds and to perform detailed mode-of-action studies, it became important to develop a reliable PAR assay that is operational with endothelial cells, which mediate the cytoprotective effects of interest. We report a detailed protocol for an intracellular calcium mobilization assay with adherent endothelial cells in multiwell plates that was used to study a number of known and new PAR1 and PAR2 ligands, including an alkynylated version of the PAR1 antagonist RWJ-58259 that is suitable for the preparation of tagged or conjugate compounds. Using the cell line EA.hy926, it was necessary to perform media exchanges with automated liquid handling equipment in order to obtain optimal and reproducible antagonist concentration-response curves. The assay is also suitable for study of PAR2 ligands; a peptide antagonist reported by Fairlie was synthesized and found to inhibit PAR2 in a manner consistent with reports using epithelial cells. The assay was used to confirm that vorapaxar acts as an irreversible antagonist of PAR1 in endothelium, and parmodulin 2 (ML161) and the related parmodulin RR-90 were found to inhibit PAR1 reversibly, in a manner consistent with negative allosteric modulation.

The invention relates to benzamide derivatives containing a 1,2,3-triazole structure shown in a general formula I as well as pharmaceutically acceptable salts, hydrates or prodrugs thereof and a preparation method thereof. Substituent groups X, Ar, R1 and

An efficient and regioselective synthesis of novel 1,2,3-triazole-fused-1,5-benzoxazocinones through intramolecular cyclization of substituted ethynyl triazoyl benzoic acids was explored. A crucial precursor 5-iodo-1,2,3-triazole benzoate was obtained fro

A mild and mass-efficient procedure based on the one-pot diazotization-azidodediazoniation of aromatic amines is described. A wide range of aryl azides are obtained in moderate to high yields by using tributyltin azide as an effective and reusable azide source in the presence of p-toluenesulfonic acid at room temperature. The method was also successfully applied employing an insoluble polymer-supported organotin azide.

The invention relates to a nitrogen heterocyclic compound having a 2-arylamine-3-aminoalkylquinazoline-4-(3H)-one structure. The nitrogen heterocyclic compound is represented as the general formula (I), wherein R1, R2, R3 and R4 are hydrogen atoms, haloge

The aim of the present study is to design and synthesize a series of novel 4(3H)-quinazolinone derivatives containing an isoxazole moiety and evaluate their antifungal activity against Gibberella zeae (G. zeae), Fusarium oxysporum (F. oxysporum), Cytospor

A facile synthesis of 1,4-disubstituted 1,2,3-triazoles was achieved from nitrobenzenes and terminal alkynes under mild conditions. The reactions were successful for nitrobenzenes and terminal alkynes bearing various functionalities, from which the 1,2,3-triazole derivatives were smoothly synthesized through a four-step one-pot sequence.

The base-mediated photochemical cyclization of 2-azidobenzoic acids with the formation of 2,1-benzisoxazole-3(1H)-ones is reported. The optimization and scope of this cyclization reaction is discussed. It is shown that an essential step of the ring closure of 2-azidobenzoic acids is the formation and photolysis of 2-azidobenzoate anions.

The progestational potency and selectivity of synthetic steroidal agonists can be enhanced by even larger chemical moieties at 17α-position of the steroid backbones. Hereby a series 5a-c and 6a-c of novel 17α-[1-(substituted phenyl)-1,2,3-triazol-4-yl]-19-nortestosterone-17β-yl acetates were designed and synthesized using click chemistry approach searching progestogenic derivatives with potential anticancer activity. Compounds 5a,b and 6a,c have affected to different extents the three histopatho-logical parameters considered for evaluation of their progestational activity. The compounds 5a,b and 6a,c showed modifications in rat uterus at 35.7-34.8 nM levels with privileged endometrial thickening effect and least change of uterine weight relative to NEA at 52.9 nM level. Up to 40 mg/kg dose compounds 5b and 6c were non-toxic. Molecular docking of the ligands in PR showed in the majority of cases a conformational fitting into the active site different from that of the reference steroid NEA. Compound 6b revealed about 46.4% growth inhibition of CNS cancer SNB-75 cell line, 56% growth inhibition of renal cancer A498 cell line and 56.7% growth inhibition of prostate cancer PC-3 cell line which was mediated by cell cycle arrest. Drugability of the screened compounds showed tolerated results after being challenged to diverse physicochemical parameters.

Azide-tethered diazocarbonyl compounds undergo copper-catalyzed conversion to transient C-acylimines. These reactive intermediates can be trapped with a variety of carbon nucleophiles, giving rise to complex 3-indolinone frameworks, including those with a

Aromatic azides are formed in high yield from arenediazonium tosylates and sodium azide in water at room temperature or from aromatic amines via diazotization in the presence of p-TsOH Besides being experimentally simple, these methods do not require any metal catalysis and provide clean products without purification. Georg Thieme Verlag Stuttgart New York.

A Staudinger/aza-Wittig reaction sequence is described that is catalytic in phosphorus. Towards this end, the phosphane oxide is reduced in situ by diphenylsilane, which allows for substoichiometric amounts of the catalyst 5-phenyldibenzophosphole to be used. The substrate scope is investigated and benzoxazoles, benzodiazepine imidates and a 2-methoxypyrrole were successfully synthesized. These investigations show that a fast aza-Wittig reaction is required to obtain high yields. A catalytic Staudinger/aza-Wittig reaction sequence, involving in situ phosphane oxide reduction, was successfully developed. Benzoxazoles, benzodiazepine imidates and 2-methoxypyrrole were synthesized without phosphane oxide waste products. Copyright

A catalyst-free, one-pot strategy for the synthesis of 1,2,3-triazole-fused 1,4-benzodiazepinone derivatives from N-substituted 2-azidobenzamides and propargyl bromide, in the presence of a base, is reported. The products are formed in good to excellent y

The effect of water admixtures on the formation of 2-oxo-(3H)-azepine-3- carboxylic acid and 2,1-benzisoxazol-3(1H)-one in the photolysis of 2-azidobenzoic acid in aprotic solvents has been investigated. It has been shown that the addition of nucleophilic

Twenty-seven novel (E)-3-[2-arylideneaminoethyl]-2-[4-(trifluoromethoxy) anilino]-4(3H)-quinazolinone derivatives were synthesized by reacting various aromatic aldehydes with intermediate 6. The target compounds were characterized by 1H NMR, s

A one-pot, efficient, and straightforward procedure for the copper-catalyzed synthesis of 1,4-disubstituted 1,2,3-triazoles is studied by in situ generation of aryl azides via the reaction of aryldiazonium silica sulfates and sodium azide, followed by coupling with a terminal alkyne. These reactions are carried out in water at room temperature without using any additional ligands.

A microwave-assisted click chemistry synthesis of 1,4-disubstituted 1,2,3-triazoles is studied by in situ generation of aryl azides via the reaction of aryldiazonium silica sulfates and sodium azide, followed by coupling with a terminal alkyne in the presence of copper catalyst. These reactions are carried out in water under mild and heterogeneous conditions without using any additional ligands.

This article describes simple and efficient method for the diazotization and azidation of different aromatic amines over cellulose sulphuric acid, sodium nitrite and sodium azide under mild conditions at room temperature. Various aryl amines possessing electron-withdrawing groups or electron-donating groups have been converted into the corresponding aryl azides with 71-99% yields. The use of mild reaction conditions, avoids the use of harmful acids and toxic solvents and short reaction times are advantages of this methodology. The selected catalyst is found to be highly efficient and recyclable.

The continuous flow synthesis of a variety of secondary amides by tandem azidation-amidation of anilines is described. This new procedure benefits from the improved safety feature of generating aromatic azides in flow, thus ensuring low concentrations of any potentially hazardous intermediates. The protocol was amenable to the production of multi-gram quantities of the amide product. Georg Thieme Verlag Stuttgart · New York.

Two sets of new conjugates obtained from d-mannose derivatives and o-, m-, and p-substituted benzoic acid esters interconnected through a triazole ring were synthesized by Cu(I) catalyzed azide-alkyne cycloaddition. All synthesized compounds were tested for their in vitro cytotoxic activity against seven cancer cell lines with/without multidrug resistance phenotype as well as non-tumor MRC-5 and BJ fibroblasts. Butyl ester of 4-aminobenzoic acid 6c showed the highest activity among all tested compounds, however, it was active only against K562 myeloid leukemia cells. N-Glycosyltriazole conjugates, both acetylated and nonacetylated at mannose moiety, were almost completely inactive. In contrast, some of the acetylated O-glycosyl conjugates showed cytotoxic activity which was cell line dependent and strongly affected by position of benzoic acid substitution as well as a length of its ester alkyl chain; the most potent compound was acetylated mannoside conjugated with octyl ester of m-substituted benzoic acid. However, deacetylation resulting in hydrophilicity increase of the glycosides almost completely abolished their cytotoxic potency.

Photolysis of aryl azides to give nitrenes, and their subsequent rearrangement in the presence of water to give 3H-azepinones, is performed in continuous flow in a photoreactor constructed of fluorinated ethylene polymer (FEP) tubing. Fine tuning of the reaction conditions using the flow reactor allowed minimization of secondary photochemical reactions.

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An efficient and highly convergent synthesis of the mitochondrial NADH oxidase inhibitor (-)-circumdatin H is described. The strategy employs the intramolecular Eguchi aza-Wittig protocol as a key step to install the crucial central core BC ring system, leading to the first total synthesis of the target molecule. Georg Thieme Verlag Stuttgart · New York.

An efficient, fast, and straightforward procedure for the synthesis of aromatic azides using aryl diazonium silica sulfates and sodium azide at room temperature under mild conditions is described. The use of inexpensive materials, simple and clean work-up

The first total synthesis of naturally occurring (Z)-11-(2-oxopropylidene)- 2,3,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-5(10H)-one,a unique cycloanthranilylproline derivative, has been achieved from readily available anthranilic acid in f

A series of 1,2-disubstituted indazol-3-ones were synthesized by microwave-assisted base-catalyzed cyclization and nucleophilic substitution of o-azidobenzanilides. Among five tested reaction conditions, the cyclization of o-azidobenzanilides catalyzed by

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We describe herein a one-pot synthesis of novel tetracyclic scaffolds that incorporate a fusion of a proline, 1,2,3-triazole ring with [1,4]-benzodiazepin-8(4H)-one ring systems following click chemistry. The expected peptide bond formation followed by in

The invention is concerned with novel benzimidazole derivatives of formula (I) wherein R1 to R8 are as defined in the description and in the claims, as well as physiologically acceptable salts and esters thereof. These compounds bind

The design and synthesis of a new diazotransfer reagent, imidazole-1-sulfonyl azide hydrochloride, are reported. This reagent has proven to equal triflyl azide in its ability to act as a "diazo donor" in the conversion of both primary amines into azides and activated methylene substrates into diazo compounds. Crucially, this reagent can be prepared in a one-pot reaction on a large scale from inexpensive materials, is shelf-stable, and is conveniently crystalline.

An efficient and improved procedure for the preparation of aromatic azides and their application in the Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition ("click reaction") is described. The synthesis of aromatic azides from the corresponding amies i

A rapid synthesis of aryl azides from the corresponding aryl halides catalyzed by CuI/diamine is described. Sodium ascorbate was found to have a positive effect on stabilization of the catalyst system. The reactions were performed under very mild conditions generally with high yields. In the case of aryl iodides, the transformation could be carried out at room temperature. Georg Thieme Verlag Stuttgart.

The application of a tricyclic pyrrolopyrimidinone scaffold for the synthesis of peptidomimetic inhibitors of interleukin-1β-converting enzyme (ICE) is reported. The synthesis of the tricyclic scaffold and conversion of it to a variety of target ICE inhib

The coupling reaction of aryl halides or vinyl iodide with sodium azide under catalysis of CuI/L-proline works at relatively low temperature to provide aryl azides or vinyl azides in good to excellent yields.

The reaction of 2-azidophenyl isocyanide (7) with [M(CO)5(thf)] (M = Cr, W) yields the isocyanide complexes [M(CO)5(7)] (M = Cr 8, M = W 9). Complexes 8 and 9 react with tertiary phosphines such as triphenylphosphane at the azido fun

A rapid analogue synthetic strategy has been developed to allow easy variation of the C-5 position of 1,2,3-triazolo[1,5-a]quinazolines. A range of directly linked and carbon tethered aromatic heterocyclic groups have been introduced utilising palladium c

A perfluoroalkyl-tagged triphenylphosphine was applied in a fluorous biphasic system for the efficient parallel synthesis of 3H-quinazolin-4-ones via an Aza-Wittig reaction. The products were isolated by solid-phase extraction on fluorous reversed-phase silica gel. A new solid-phase bound phosphine derivative was used for comparison and yielded similar results.