Recent Progress on Synthesis of Functionalized 1,5-Disubstituted Triazoles.

Immediately after the invention of 'Click Chemistry' in 2002, the regioselective 1,2,3- triazole scaffolds resulted from respective organic azides and terminal alkynes under Cu(I) catalysis have been well recognized as the functional heterocyclic core at the centre of modern organic chemistry, medicinal chemistry, and material sciences. This CuAAC reaction has several notable features including excellent regioselectivity, high-to-excellent yields, easy to execute, short reaction time, modular in nature, mild condition, readily available starting materials, etc. Moreover, the resulting regioselective triazoles can serve as amide bond isosteres, a privileged functional group in drug discovery and development. More than hundreds of reviews had been devoted to the 'Click Chemistry' in special reference to 1,4-disubstituted triazoles, while only little efforts were made for an opposite regioisomer i.e., 1,5-disubstituted triazole. Herein, we have presented various classical approaches for an expeditious synthesis of a wide range of biologically relevant 1,5- disubstituted 1,2,3-triazole analogues. The syntheses of such a class of diversly functionalized triazoles have emerged as a crucial investigation in the domain of chemistry and biology. This tutorial review covers the literature assessment on the development of various synthetic protocols for the functionalized 1,5-disubstituted triazoles reported during the last 12 years.

Design, synthesis, and docking study of saccharin N-triazolyl glycoconjugates.

To achieve better-repurposed motifs, saccharin has been merged with biocompatible sugar molecules via a 1,2,3-triazole linker, and ten novel 1,2,3-triazole-appended saccharin glycoconjugates were developed in good yield by utilizing modular CuAAC click as regioselective triazole forming tool. The docking study indicated that the resulting hybrid molecules have an overall substantial interaction with the CAXII macromolecule. Moreover, the galactose triazolyl saccharin analogue 3h has a binding energy of -8.5 kcal/mol with 5 H-bonds, and xylosyl 1,2,3-triazolyl saccharin analogue 3d has a binding energy of -8.2 kcal/mol with 6 H-bond interactions and have exhibited the highest binding interaction with the macromolecule system.

Triazole-Appended Glycohybrid/CuI-Catalyzed C-C Cross-Coupling of Aryl/Heteroaryl Halides with Alkynyl Sugars.

This report describes a convenient method for the Cu(I)-catalyzed Sonogashira cross-coupling reaction of aryl/heteroaryl halides and alkynyl sugars in the presence of a 1,2,3-triazole-appended glycohybrid as a biocompatible ligand. The Sonogashira cross-coupling products were exclusively formed without the Glaser-Hay homocoupling reaction in the presence of a glycosyl monotriazolyl ligand at 120 °C. However, the Glaser-Hay homocoupling products were obtained at 60-70 °C in the presence of bis-triazolyl-based macrocyclic glycohybrid ligand L8. The glycosyl triazole ligands were synthesized via the CuI/DIPEA-mediated regioselective CuAAC click reaction, and a series of glycohybrids of glucose, mannose, and galactose alkynes including glycosyl rods were developed in good yields. The developed glycohybrids have been well characterized by various spectroscopic techniques, such as nuclear magnetic resonance, high-resolution mass spectrometry, and single-crystal X-ray data of L3. The protocol works well with the heteroaryl and naphthyl halides, and the mechanistic approach leads to CuI/ligand-assisted oxidative coupling. The coupling protocol has notable features, including low catalytic loading, cost-effectiveness, biocompatible nature, and a wide substrate scope.

Organocatalyzed Regioselective Synthesis of 1,5-Disubstituted 1,2,3-Triazolyl Glycoconjugates.

A novel organocatalyzed [3+2] cycloaddition reaction of nitroolefins with glycosyl azides as well as organic azides has been developed for successful construction of 1,5-disubstituted triazolyl glycoconjugates. This metal-free and acid-free, regioselective synthetic protocol proceeds in the presence of only Schreiner thiourea organocatalysts, which enable the required activation of nitroolefins through double hydrogen bonding. The straightforward, operationally simple, and regioselectivity of this methodology, complementing to the classical RuAAC catalyzed synthesis of 1,5-disubstituted 1,2,3-triazoles. In the presence of catalytic amount of Schreiner thiourea organocatalyst, organic azides react with a broad array of nitroolefins producing a series of diverse 1,5-disubstituted 1,2,3- triazoles in good yields with excellent regioselectivity.

Design, Synthesis, and Docking Study of Quinine-9-Triazolyl Conjugates.

To develop a better chemotherapeutically potential candidate for lung cancer treatment and cure with repurposed motifs, quinine has been linked with biocompatible CuAAC-inspired regioselective 1,2,3-triazole linker and a series of ten novel 1,2,3-triazolyl-9-quinine conjugates have been developed by utilizing click conjugation of glycosyl ether alkynes with 9-epi-9-azido-9-deoxy-quinine under standard click conditions. In parallel, the docking study indicated that the resulting conjugates have an overall appreciable interaction with ALK-5 macromolecules. Moreover, the mannose-triazolyl conjugate exhibited the highest binding interactions of -7.6 kcal/mol with H-bond interaction with the targeted macromolecular system and indicate the hope for future trials for anti-lung cancer candidates.

Growing Impact of Intramolecular Click Chemistry in Organic Synthesis.

Click Chemistry, a modular, rapid, and one of the most reliable tool for the regioselective 1,2,3-triazole forming [3+2] reaction of organic azide and terimal alkyne is widely explored in various emerging domains of research ranging from chemical biology to catalysis and medicinal chemistry to material science. This regioselective reaction from a diverse range of azido-alkyne scaffolds has been well performed in both intermolecular as well as intramolecular fashions. In comparison to the intermolecular metal (Cu/Ru/Ni) variant of 'Click Chemistry', the intramolecular click tool is little addressed. The intramolecular click chemistry is exemplified as a mordern tool of cyclization which involves metal-catalyzed (CuAAC/RuAAC) cyclization, organo-catalyzed cyclization, and thermal-induced topochemical reaction. Thus, we report herein the recent approaches on intramolecular azide-alkyne cycloaddition 'Click Chemistry' with their wide-spread emerging applications in the developement of a diverse range of molecules including fused-heterocycles, well-defined peptidomemics, and macrocyclic architectures of various notable features.

Click inspired synthesis of piperazine-triazolyl sugar-conjugates as potent anti-Hela activity.

To imbibe the aim of synthesizing water-soluble and biocompatible motif, a click-inspired piperazine glycoconjugate has been devised up. In this report, we present a focused approach to design and synthesis of versatile sugar-appended triazoles through 'Click Chemistry' along with their pharmacological studies on cyclin-dependent kinases (CDKs) and cell cytotoxicity on cancer cells using in silico and in vitro approaches, respectively. The study has inclusively recognized the galactose- and mannose-derived piperazine conjugates as the promising motifs. The findings suggested that the galactosyl bis-triazolyl piperazine analogue 10b is the most CDK interactive derivative and also possess significant anticancer activity.

Growing impact of sialic acid-containing glycans in future drug discovery.

In nature, almost all cells are covered with a complex array of glycan chain namely sialic acids or nuraminic acids, a negatively charged nine carbon sugars which is considered for their great therapeutic importance since long back. Owing to its presence at the terminal end of lipid bilayer (commonly known as terminal sugars), the well-defined sialosides or sialoconjugates have served pivotal role on the cell surfaces and thus, the sialic acid-containing glycans can modulate and mediate a number of imperative cellular interactions. Understanding of the sialo-protein interaction and their roles in vertebrates in regard of normal physiology, pathological variance, and evolution has indeed a noteworthy journey in medicine. In this tutorial review, we present a concise overview about the structure, linkages in chemical diversity, biological significance followed by chemical and enzymatic modification/synthesis of sialic acid containing glycans. A more focus is attempted about the recent advances, opportunity, and more over growing impact of sialosides and sialoconjugates in future drug discovery and development.

Click Chemistry Inspired Synthesis of Hydroxyanthracene Triazolyl Glycoconjugates.

Novel hydroxyanthracene-based terminal alkynes 3 and 5a/b were synthesized by the acetylide addition reaction at the 9,10-position of anthraquinone 1 under mild conditions. The developed alkynes 3, 5a, and 5b on Huisgen azide-alkyne cycloaddition reaction with azido-sugars 6 in the presence of Cu(I) catalyst provided a series of triazole fasten hydroxyanthracene glycoconjugates 7, 8, and 9, respectively, in good yields. The representative compounds 9 and 7h were successfully deprotected under room-temperature conditions to liberate the corresponding free glycoconjugates 10 and 11, respectively. Further, structures of a few compounds were unmaliciously evidenced by their single-crystal X-ray.

Pyridyl Glycosyl Triazole/CuI-Mediated Domino/Tandem Synthesis of Quinazolinones.

The glycosyl 1,2,3-triazoles are expediently accessible from readily available sugar-derived glycosyl azide by utilizing modular CuAAC "Click Chemistry", and the resulting glycohybrid skeleton possesses efficient metal-coordinating centers that support a wide range of metal-mediated efficient catalysis in various imperative organic transformations. Here, we designed and developed pyridyl glycosyl triazoles by employing the CuAAC reaction of d-glucose-derived glycosyl azides and alkynyl pyridines. These pyridyl glycosyl triazoles with Cu(I) salt were explored as an efficient catalyst to successfully assemble 2-amino-3-substituted and 3-substituted quinazolinones by the domino/tandem cross-coupling reaction of various N-substituted o-halobenzamides with cyanamide and formamide, respectively. The devised protocol has some notable features, including biocompatibility, low cost, easily accessible starting materials for the glycosyl ligands, high yield, broad spectrum, low catalytic loading, and mild reaction conditions.

One-pot expeditious synthesis of glycosylated esters through activation of carboxylic acids using trichloroacetonitrile.

Acetimidates, a valuable intermediate has been well explored as versatile synthon in a number of organic transformations particularly as suitable donors in glycosylation reactions. Herein, we explored acetimidates to furnish high-to-excellent yield of diverse glycosylated esters under one-pot mild reaction condition. The commercially available trichloroacetonitrile is implemented for the activation of carboxylic acid via in situ generation of trichloroacetimidate, which was subsequently attacked by sugar alcohols to deliver high-to-excellent yields of desired glycosylated esters. The devised method has some notable features such as metal-free condition, one-pot mild reaction condition, easy-handling, high-to-excellent yields, and broad substrate scope.

Emerging impact of triazoles as anti-tubercular agent.

Tuberculosis, a disease of poverty is a communicable infection with a reasonably high mortality rate worldwide. 10 Million new cases of TB were reported with approx 1.4 million deaths in the year 2019. Due to the growing number of drug-sensitive and drug-resistant tuberculosis cases, there is a vital need to develop new and effective candidates useful to combat this deadly disease. Despite tremendous efforts to identify a mechanism-based novel antitubercular agent, only a few have entered into clinical trials in the last six decades. In recent years, triazoles have been well explored as the most valuable scaffolds in drug discovery and development. Triazole framework possesses favorable properties like hydrogen bonding, moderate dipole moment, enhanced water solubility, and also the ability to bind effectively with biomolecular targets of M. tuberculosis and therefore this scaffold displayed excellent potency against TB. This review is an endeavor to summarize an up-to-date innovation of triazole-appended hybrids during the last 10 years having potential in vitro and in vivo antitubercular activity with structure activity relationship analysis. This review may help medicinal chemists to explore the triazole scaffolds for the rational design of potent drug candidates having better efficacy, improved selectivity and minimal toxicity so that these hybrid NCEs can effectively be explored as potential lead to fight against M. tuberculosis.

Glycosyl Triazole Ligand for Temperature-Dependent Competitive Reactions of Cu-Catalyzed Sonogashira Coupling and Glaser Coupling.

Glycosyl triazoles have been introduced as efficient ligands for the Cu-catalyzed Sonogashira reaction to overcome the challenges of sideways homocoupling reactions in Cu catalysis in this reaction. The atmospheric oxygen in a sealed tube did not affect the coupling, and no need of complete exclusion of oxygen was experienced in the presence of glycohybrid triazole ligand L3. High product yields were obtained at 130 °C for a variety of substrates including aliphatic and aromatic terminal alkynes and differently substituted aromatic halides including 9-bromo noscapine. In contrast, at room temperature, a very low loading of the L3-Cu catalytic system could produce excellent yields in Glaser coupling including homocoupling and heterocoupling of a variety of aliphatic and aromatic alkynes.

d-Glucosamine as the Green Ligand for Cu(I)-Catalyzed Regio- and Stereoselective Domino Synthesis of (Z)-3-Methyleneisoindoline-1-ones and (E)-N-Aryl-4H-thiochromen-4-imines.

d-Glucosamine, a natural, inexpensive, and conveniently accessible sugar, has been explored as an efficient ligand for the Cu(I)-catalyzed regio- and stereoselective synthesis of an array of (Z)-3-methyleneisoindoline-1-ones and (E)-N-aryl-4H-thiochromen-4-imines in good-to-excellent yield in a tandem fashion via the reaction of 2-halobenzamide and 2-halobenzothioamide with terminal alkynes, respectively. The water solubility and biocompatible nature of the ligand offer easy separation of the catalytic system toward the aqueous phase as well as change in the reaction path in terms of the product also demonstrated the variation of the reaction temperature. The domino reaction proceeds by the Sonogashira and Ullmann type cross-coupling reaction, followed by Cu(I)-promoted additive cyclization of heteroatom to the triple bond. In addition, d-glucosamine causes successful Glaser-Hay coupling of terminal alkynes under Cu catalysis to produce a high yield of respective 1,3-diynes.

CuAAC mediated synthesis of cyclen cored glycodendrimers of high sugar tethers at low generation.

Glycodendrimers are receiving considerable attention to mimic a number of imperative features of cell surface glycoconjugate and acquired excellent relevance to a wide domain of investigations including medicine, pharmaceutics, catalysis, nanotechnology, carbohydrate-protein interaction, and moreover in drug delivery systems. Toward this end, an expeditious, modular, and regioselective triazole-forming CuAAC click approach along with double stage convergent synthetic method was chosen to develop a variety of novel chlorine-containing cyclen cored glycodendrimers of high sugar tethers at low generation of promising therapeutic potential. We developed a novel chlorine-containing hypercore unit with 12 alkynyl functionality originated from cyclen scaffold which was confirmed by its single crystal X-ray data analysis. Further, the modular CuAAC technique was utilized to produce a variety of novel 12-sugar coated (G0) glycodendrimers 12-15 adorn with ß-Glc-, ß-Man-, ß-Gal-, ß-Lac, along with 36-galactose coated (G1) glycodendrimer 18 in good-to-high yield. The structures of the developed glycodendrimer architectures have been well elucidated by extensive spectral analysis including NMR (1H & 13CNMR), HRMS, MALDI-TOF MS, UV-Vis, IR, and SEC (Size Exclusion Chromatogram) data.

Cu(I)-Catalyzed Click Chemistry in Glycoscience and Their Diverse Applications.

Copper(I)-catalyzed 1,3-dipolar cycloaddition between organic azides and terminal alkynes, commonly known as CuAAC or click chemistry, has been identified as one of the most successful, versatile, reliable, and modular strategies for the rapid and regioselective construction of 1,4-disubstituted 1,2,3-triazoles as diversely functionalized molecules. Carbohydrates, an integral part of living cells, have several fascinating features, including their structural diversity, biocompatibility, bioavailability, hydrophilicity, and superior ADME properties with minimal toxicity, which support increased demand to explore them as versatile scaffolds for easy access to diverse glycohybrids and well-defined glycoconjugates for complete chemical, biochemical, and pharmacological investigations. This review highlights the successful development of CuAAC or click chemistry in emerging areas of glycoscience, including the synthesis of triazole appended carbohydrate-containing molecular architectures (mainly glycohybrids, glycoconjugates, glycopolymers, glycopeptides, glycoproteins, glycolipids, glycoclusters, and glycodendrimers through regioselective triazole forming modular and bio-orthogonal coupling protocols). It discusses the widespread applications of these glycoproducts as enzyme inhibitors in drug discovery and development, sensing, gelation, chelation, glycosylation, and catalysis. This review also covers the impact of click chemistry and provides future perspectives on its role in various emerging disciplines of science and technology.

Development of Diverse Range of Biologically Relevant Carbohydrate-Containing Molecules: Twenty Years of Our Journey*.

There is an increasing demand for significant amount of carbohydrate-containing molecules owing to their complete chemical, biological, and pharmacological investigations to better understand their role in many important biological events. Clinical studies of a wide range of simple carbohydrates or their derivatives, glycohybrids, glycoconjugates, and neoglycoconjugates have been conducted worldwide for the successful treatment of various frontline diseases. Herein, a brief perspective of carbohydrate-based molecular scaffolding and my experience during the last 20 years in the area of synthetic carbohydrate chemistry, mainly for their impact in drug discovery & development, is presented.

Synthesis of a Series of a Few Hydrosulfide Complexes of Cu(I). A µ3-SH-Bridged Rare Cubane-like Tetramer Showing Efficient Catalytic Activity toward Azide-Alkyne Cycloaddition.

A cubane-like tetranuclear hydrosulfido complex of Cu(I), [Cu4(SH)4(PPh3)4] (1), has been synthesized by the reaction of Cu(NO3)2·3H2O, NaSCOPh, and Cu(PPh3)2NO3 and characterized structurally. Complex 1 represents the first example of crystallographically characterized µ3-SH-bridged cubanoid hydrosulfide. By direct reactions of [(PPh3)2Cu(NO3)] and NaSH, neutral hydrosulfide complexes [Cu(SH)(PPh3)2]·C6H6 (2), [Cu2(SH)2(PPh3)3] (3), and [Cu2(SH)2(PPh3)4] (4) have also been synthesized and structurally characterized. Complex 2 is monomeric with a terminal hydrosulfide ligand. The other two, 3 and 4, are µ2-SH-bridged unsymmetrical and symmetrical dinuclear complexes, respectively. In the symmetric one (4), both Cu(I) ions are tetrahedrally coordinated while in the unsymmetric one (3), one Cu(I) ion is tetrahedral and the other one has a trigonal-planar coordination geometry. The catalytic activity of a hydrosulfido complex in a "click" azide-alkyne cycloaddition reaction has been explored for the first time, and complex 1 is found to be an efficient catalyst for the regioselective synthesis of glycoconjugate triazoles.

Click Inspired Synthesis of Novel Cinchonidine Glycoconjugates as Promising Plasmepsin Inhibitors.

Among all the malaria parasites, P. falciparum is the most predominant species which has developed drug resistance against most of the commercial anti-malarial drugs. Thus, finding a new molecule for the inhibition of enzymes of P. falciparum is the pharmacological challenge in present era. Herein, ten novel molecules have been designed with an amalgamation of cinchonidine, carbohydrate moiety and triazole ring by utilizing copper-catalyzed click reaction of cinchonidine-derived azide and clickable glycosyl alkynes. The molecular docking of developed molecules showed promising results for plasmepsin inhibition in the form of effective binding with target proteins.