Open access peer-reviewed chapter

1,2,3-Triazoles: Synthesis and Biological Application

Written By

Abdul Aziz Ali

Submitted: 26 November 2019 Reviewed: 28 April 2020 Published: 13 October 2020

DOI: 10.5772/intechopen.92692

From the Edited Volume

Azoles - Synthesis, Properties, Applications and Perspectives

Edited by Aleksey Kuznetsov

Chapter metrics overview

1,680 Chapter Downloads

View Full Metrics

Abstract

Among nitrogen-containing heterocyclic compounds, 1,2,3-triazoles are privileged structure motif and received a great deal of attention in academics and industry. Even though absent in nature, 1,2,3-triazoles have found broad applications in drug discovery, organic synthesis, polymer chemistry, supramolecular chemistry, bioconjugation, chemical biology, fluorescent imaging, and materials science. Therefore, the development of facile and straightforward methodology for the synthesis of 1,2,3-triazoles is of noteworthy interest. In this study, emphasis will be given to numerous synthetic approaches for the synthesis of 1,2,3-triazoles, especially the popular click chemistry approach. Furthermore, several biological activities of this promising heterocycle will also be discussed.

Keywords

  • 1
  • 2
  • 3-triazoles
  • click chemistry
  • organocatalysis
  • biological activity
  • drug discovery

1. Introduction

Nitrogen-containing heterocyclic compounds are indispensable for life as they are part of essential building blocks like amino acids, nucleotides, etc. 1,2,3-Triazoles are one of the most important nitrogen-containing five-membered heterocycles and have a wide range of applications in pharmaceuticals, supramolecular chemistry, organic synthesis, chemical biology and industry [1, 2, 3, 4, 5, 6]. The 1,2,3-triazoles has numerous useful properties like high chemical stability (usually inert to acidic or basic hydrolysis as well as oxidizing and reducing conditions even at high temperature), aromatic character, strong dipole moment (4.8–5.6 Debye), and hydrogen bonding ability [7]. These spectacular features make the substituted 1,2,3-triazole motif structurally resembling to the amide bond, mimicking an E or a Z amide bond. Many prominent medicinal compounds having a 1,2,3-triazole core are available in the market like anticonvulsant drug Rufinamide, broad spectrum cephalosporin antibiotic cefatrizine, an anticancer drug carboxyamidotriazole and β-lactum antibiotic tazobactam, etc. [8].

Advertisement

2. Synthesis of 1,2,3-triazoles

Owing to its versatile applications, the synthesis of 1,2,3-triazoles has been a subject of extensive research. The synthetic methodologies for the preparation of this important scaffold can be broadly divided into four categories (Figure 1) [9]:

  1. Huisgen 1,3-dipolar cycloaddition

  2. Metal-catalyzed 1,3-dipolar cycloaddition

  3. Strain-promoted azide alkyne cycloaddition

  4. Metal-free synthesis of 1,2,3-triazoles

Figure 1.

Strategy of the synthesis of 1,2,3-triazoles.

2.1 Huisgen 1,3-dipolar cycloaddition

Huisgen 1,3-dipolar cycloaddition was the most straightforward and atom-economical synthesis of 1,2,3-triazoles. However, elevated reaction temperature and poor regioselectivity (mixtures of 1,4- and 1,5-isomers) make this process unsatisfactory [10].

2.2 Metal-catalyzed 1,3-dipolar cycloaddition

In 2001, Sharpless et al. coined the term “Click Chemistry,” a set of highly reliable, practical, and selective reactions for the rapid synthesis of valuable new compounds and combinatorial libraries. The click reaction should be modular, with high yield, wide in scope, generate only innocuous by-products (that can be removed without chromatography), stereospecific, easy to carry out and that need benign solvent [11]. In 2002, the groups of Sharpless and Meldal independently revealed a copper-catalyzed variant of Huisgen’s azide-alkyne cycloaddition (CuAAC reaction) identified as one of the prime example of click chemistry in the literature [12, 13]. The unique advantages of CuAAC reaction are excellent substrate scope, prominent atom economy, good regioselectivity (only 1,4-isomer), high yield of products and mild reaction conditions [14, 15, 16, 17].

In 2005, Fokin and coworkers devised an efficient approach for the construction of 1,5-disubstituted 1,2,3-triazoles by ruthenium cyclopentadienyl complexes (RuAAC). In addition, internal alkynes also effective in this protocol leading to fully substituted 1,2,3-triazoles [18].

The McNulty group reported a well-defined Ag(I) complex for the regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles at room temperature [19].

An interesting Zn(OAc)2-catalyzed azide-alkyne cycloaddition was developed by Postnikov and his research group affording 1,4-disubstituted 1,2,3-triazoles [20].

In 2017, Kim et al. devised Cp2Ni/Xantphos catalytic method to access 1,5-disubstituted 1,2,3-triazoles under mild condition [21].

Sun and coworkers reported intermolecular iridium-catalyzed azide-alkyne cycloaddition reaction (IrAAC) of electron-rich internal alkynes [22].

2.3 Strain-promoted azide alkyne cycloaddition

Despite the overwhelming popularity of click chemistry in modern science and technology, the using of metals creates serious concern in biological system due to cellular toxicity. The Bertozzi group explored an interesting protocol of strain-promoted azide-alkyne cycloaddition (SPAAC) reaction for bioconjugation. The driving force for this reaction was the release of large ring strain in the cycloalkynes which proceeds under physiological condition without any catalyst [23].

2.4 Metal free synthesis of 1,2,3-triazoles

Organocatalytic reactions has gained considerable attention in the synthesis of 1,2,3-triazoles using enamines, enolates as dipolarophiles. Besides, activated alkenes were established as a useful substrate for triazole formation.

Ramachary and coworkers developed L-proline-catalyzed synthesis of 1,2,3-triazoles via an enamine mediated [3 + 2]-cycloaddition reaction [24].

In 2011, the regioselective synthesis of 1,4,5-trisubstituted 1,2,3-triazoles was achieved by Wang et al. using an organocatalytic enamine azide reaction [25].

The Bressy group reported synthesis of substituted 1,2,3-triazoles from unactivated ketone and aromatic azide using microwave condition [26].

Wang and coworkers devised an organocatalytic method for the preparation of fully substituted 1,2,3-triazoles by diethylamine-catalyzed reaction of azides and allyl ketones [27].

Iodine mediated, oxidant free synthesis of 1,5-disubstituted 1,2,3-triazoles was reported by the Wan group using primary amines, enamines and tosylhydrazine [28].

Using potassium carbonate, Kannan and co-workers developed a protocol for the synthesis of 4-acetyl-5-methyl-1,2,3-triazoles from acetylacetone and aromatic azides [29].

The Ramachary group described an efficient methodology for the preparation of 1,4-disubstituted 1,2,3-triazoles using organocatalytic azide-aldehyde [3 + 2] cycloaddition reaction [30].

Paixão et al. reported the use of alkylidenemalononitriles in 1,3-dipolar cycloaddition with aromatic azides mediated by DBU [31].

In their another pioneering work, Ramachary and coworkers reported an interesting organocatalytic [3 + 2]-cycloaddition reaction of ketones with azides for synthesis of fully substituted 1,2,3-triazoles [32].

In a methodology published in 1986, Sakai et al. used primary amines and α,α-dichloro ketone derived tosylhydrazones for the metal free synthesis of 1,2,3-triazoles [33].

Westermann and co-workers developed a cascade reaction using α,α-dichlorotosylhydrazones and primary amines in the presence of diisopropylethylamine [34].

Metal free regioselective synthesis of 1,4,5-trisubstituted 1,2,3-triazoles was reported by Dehaen et al. from aldehydes, nitroalkanes and organic azides [35].

The Guan group developed p-toluenesulfonic acid-catalyzed 1,3-dipolar cycloaddition reaction for the synthesis of 4-aryl-NH-1,2,3-triazoles from nitroolefins with sodium azide [36].

Advertisement

3. Biological activity of 1,2,3-triazoles

1,2,3-triazoles are stable towards metabolic degradation and easily form hydrogen bonding which can increase solubility favoring the binding of biomolecular targets. Owing to their unique properties, 1,2,3-triazoles are attractive building blocks in drug discovery.

3.1 Anti-cancer activity

Cancer is a major public health concern and second leading cause of mortality globally. Despite that numerous anticancer agents including taxol, vincristine, vinblastine, camptothecin derivatives, topotecan are available, search for novel compounds with different modes of actions has received significant interest.

Kallander et al. reported 4-aryl-1,2,3-triazoles 1 as inhibitors of human methionine aminopeptidase type 2 (hMetAP2). The anticancer activity of these molecules is due to the N1 and N2 nitrogen atoms of the triazole moiety that actively contribute in binding to the active site of enzyme [37].

Odlo and coworkers disclosed a series of cis-restricted 1,5-disubstituted 1,2,3-triazole analogues of combretastatin A-4. One of the triazole derivatives 2 showed effective cytotoxic activity against various cancer cell lines with IC50 values in the nanomolar range. Molecular docking study shows that the triazole moiety interacts with β-tubulin via H-bonding with numerous amino acids [38].

The series of triazole-modified 20,30-dideoxy-20,30-diethanethioribonucleosides 3 displayed considerably better antitumor activity towards HepG2, A549, and Hela cell lines and higher cytotoxicity towards HepG2, LAC, and Hela cell lines compared to the control drug floxuridine [39].

Rangappa and coworkers prepared a series of 1,2-benzisoxazole tethered 1,2,3-triazoles 4 and established its noteworthy antiproliferative effect against human acute myeloid leukemia (AML) cells. Using MTT assay, 3-(4-(4-phenoxyphenyl)-1H-1,2,3-triazol-1-yl)benzo[d]isoxazole was found to be the most potent antiproliferative agent with an IC50 of 2μM against MV4-11 cells [40].

Using “click chemistry” approach, the Miller group prepared a series of N-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)arylamides and examined their antiproliferative activity. One of the compound 5 displayed an IC50 of 46 nM against MCF-7 human breast tumor cells [41].

Lin and coworkers synthesized a series of heterocycle-fused 1,2,3-triazoles and evaluated their cytotoxic activity. With IC50 values lower than 1.9μg/mL against A431 and K562 human tumor cell lines, 4-Methoxyphenyl substituted 1,3-oxazoheterocycle fused 1,2,3-triazole 6 was found to be the most potent derivative [42].

1,2,3-triazole derivatives of betulinic acid were synthesized by Koul et al. and their cytotoxic activity against nine human cancer cell lines was evaluated (Figure 2). Two molecules 7 and 8 exhibited notable IC50 values (2.5 and 3.5μM, respectively) against leukemia cell line HL-60 (5–7-fold higher potency than betulinic acid) [43].

Figure 2.

Some examples of 1,2,3-triazole containing molecules with anticancer activity.

3.2 Anti-inflammatory activity

Inflammation is particularly complex biological process of body tissues, where membrane-bound phospholipids release arachidonic acid (AA), followed by biotransformation processes using cycloxygenase (COX) and 5-lipoxygenase (5-LOX) pathways. Several non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin, ibuprofen, and naproxen block arachidonic acid metabolism by obstructing cycloxygenase. Nevertheless the side effects associated with these drugs prompted medicinal chemists to develop alternative scaffolds.

The Jung group synthesized twenty-four phenyl-1H-1,2,3-triazole derivatives and studied their biological activity. At the same dose of 25 mg/kg, compound 9 showed more compelling effects than the existing anti-inflammatory drug diclofenac [44].

Yar and coworkers reported 1,2,3-triazole tethered Indole-3-glyoxamide derivatives for in vivo anti-inflammatory activity using click chemistry approach. Two compounds 10 and 11 displayed excellent inhibition of COX-2 (IC500.12µM) with good COX-2 selectivity index (COX-2/COX-1) of 0.058 and 0.046, respectively (Figure 3) [45].

Figure 3.

Various examples of 1,2,3-triazole containing molecules with anti-inflammatory activity.

3.3 Antitubercular activity

Tuberculosis (TB) caused by Mycobacterium tuberculosis is one of the infectious contagious disease and remains a serious risk to public health worldwide. Generally, the direct observed therapy strategy (DOTS) is the treatment for TB, but the emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) developed challenges. Therefore identifying of effective anti-TB drug candidates has received enormous interest.

Labadie and coworkers used click chemistry to synthesize a small library of 1,2,3-triazole derivatives and screened them against Mycobacterium tuberculosis and Mycobacterium avium. The biological screening indicated that the triazole 12 displayed more significant activity against M. tuberculosis than standard drug [46].

Using click chemistry, the Boechat group reported 4-substituted N-phenyl-1,2,3-triazole derivatives for antimicrobial activity against Mycobacterium tuberculosis strain H37Rv (ATCC 27294). Derivatives of isoniazid, (E)-N′-[(1-aryl)-1H-1,2,3-triazole-4-yl)methylene] isonicotinoyl hydrazides, 13 revealed significant activity with minimum inhibitory concentration (MIC) value of 0.62μg/mL [47].

The Kantevari group described a molecular hybridization approach for the synthesis of triazole clubbed dibenzo[b,d]thiophene-based Mycobacterium tuberculosis inhibitors. The most potent compounds 14 and 15 in check of their in vitro activity against M. tuberculosis strain H37Rv exhibited MIC=0.78μg/mL [48].

Zhang et al. synthesized triazole-based library of benzofuran salicylic acid derivatives using click chemistry strategy. The compound 16 was found to be potent antiTB therapeutic with efficient cellular activity (Figure 4) [49].

Figure 4.

Representative examples of 1,2,3-triazole containing molecules with antitubercular activity.

3.4 Antimicrobial activity

Fungal and bacterial infections create severe apprehension for human and animal survival. The inefficacy of available drugs and rising resistant strains demand significant interest into new classes of antimicrobial agents.

Agarwal and coworkers synthesized 1,2,3-triazole derivatives of chalcones and flavones by click chemistry and screened their antimicrobial and antiplasmodial activity. Several compound including 17 showed promising antifungal and antibacterial activity [50].

The Murugulla group studied antimicrobial activity of theophylline containing 1,2,3-triazoles with variant nucleoside derivatives. Compound 18 was shown to be potent and effective against three bacterial strains B. cereus, Escherichia coli and P. aureoginosa with MIC values of 0.0156, 0.03125, 0.0625 mg/mL and compound 19 with MIC values of 0.03125, 0.0156, 0.0625 mg/mL was found to be effective against S. aureus, B. cereus and Escherichia coli, respectively [51].

Diaryl sulfone containing novel 1,2,3-triazoles were synthesized by Jørgensen and coworkers and their biological evaluation was carried out as well. Compound 20 was found to be the most potent antifungal agents with MIC at 25μg/mL [52].

Zhou et al. reported a series of 1,2,3-triazole-derived naphthalimides for potential antimicrobial activity. Bioactive assay revealed that 21 showed better anti-Escherichia coli activity than existing drugs Norfloxacin and Chloromycin [53].

5-nitrofuran—triazole congener—was prepared by the Kamal group and its biological activity was studied. Among the other compounds, 22 exhibited promising antibacterial activity (MIC value of 1.9μg/mL against different bacterial strains) and antifungal activity (MIC=3.9μg/mL) compared to the standard miconazole (MIC=7.8μg/mL) against C. albicans and C. parapsilosis (Figure 5) [54].

Figure 5.

Representative examples of 1,2,3-triazole containing molecules with antimicrobial activity.

3.5 Antiviral activity

Viral diseases are caused by viruses infecting an organism body. Although vaccines and antiviral drugs are used for treating viral infections, advance of novel viruses creates health risk over the world. Therefore development of alternative antiviral agents is of significant interest.

Boechat and coworkers reported the synthesis of 1,2,3-triazole nucleoside ribavirin analogs and studied their antiviral activity. The synthesized compound 23 displayed potent activity with IC50 values 14 and 3.8 μM for Influenza A and reverse transcriptase (RT) from human immunodeficiency virus type 1 (HIV-1 RT), respectively [55].

Ribavirin analogues—4,5-disubstituted 1,2,3-triazole nucleosides—were synthesized by Zeidler et al. and screened for their biological activity. 5-ethynyl nucleoside 24 exhibited effective virus-inhibitory activity against influenza A (H1N1, H3N2 and H5N1), influenza B, measles and respiratory syncytial viruses [56].

The Ding group targeted virus nucleoprotein and synthesized 1,2,3-triazole-4-carboxamide derivatives for anti-influenza drug development. The compound 25, inhibited the replication of various H3N2 and H1N1 influenza A virus strains with IC50 values ranging from 0.5 to 4.6 μM (Figure 6) [57].

Figure 6.

Examples of 1,2,3-triazole containing molecules with antiviral activity.

Advertisement

4. Conclusion

In summary, 1,2,3-triazole moiety has proven to be a privileged scaffolds in medicinal chemistry. The exceptional properties of this promising heterocycle facilitate its wide range of applications from material science to bioconjugation. Thanks to Sharpless for introducing “Click Chemistry,” one of the most prevailing tools in drug discovery, chemical biology, and proteomic applications and undoubtedly opens new avenue to the scientific community towards the improvement of life.

Advertisement

Acknowledgments

The author is thankful for the financial support by CSIR, New Delhi, India.

Advertisement

Conflict of interest

There are no conflicts to declare.

References

  1. 1. Dheer D, Singh V, Shankar R. Medicinal attributes of 1,2,3-triazoles: Current developments. Bioorganic Chemistry. 2017;71:30-54. DOI: 10.1016/j.bioorg.2017.01.010
  2. 2. Schulze B, Schubert US. Beyond click chemistry–Supramolecular interactions of 1,2,3-triazoles. Chemical Society Reviews. 2014;43:2522-2571. DOI: 10.1039/C3CS60386E
  3. 3. Liang L, Astruc D. The copper (I)-catalyzed alkyne-azide cycloaddition (CuAAC)“click” reaction and its applications. An overview. Coordination Chemistry Reviews. 2011;255:2933-2945. DOI: 10.1016/j.ccr.2011.06.028
  4. 4. Ngo JT, Adams SR, Deerinck TJ, Boassa D, Rodriguez-Rivera F, Palida SF, et al. Click-EM for imaging metabolically tagged nonprotein biomolecules. Nature Chemical Biology. 2016;12:459-465. DOI: 10.1038/nchembio.2076
  5. 5. Astruc D, Liang L, Rapakousiou A, Ruiz J. Click dendrimers and triazole-related aspects: Catalysts, mechanism, synthesis, and functions. A bridge between dendritic architectures and nanomaterials. Accounts of Chemical Research. 2012;45:630-640. DOI: 10.1021/ar200235m
  6. 6. Wang X, Huang B, Liu X, Zhan P. Discovery of bioactive molecules from CuAAC click-chemistry-based combinatorial libraries. Drug Discovery Today. 2016;21:118-132. DOI: 10.1016/j.drudis.2015.08.004
  7. 7. Meldal M, Tornøe CW. Cu-catalyzed azide−alkyne cycloaddition. Chemical Reviews. 2008;108:2952-3015. DOI: 10.1021/cr0783479
  8. 8. Agalave SG, Maujan SR, Pore VS. Click chemistry: 1,2,3-Triazoles as pharmacophores. Chemistry – An Asian Journal. 2011;6:2696-2718. DOI: 10.1002/asia.201100432
  9. 9. Jalani HB, Karagöz AÇ, Tsogoeva SB. Synthesis of substituted 1,2,3-triazoles via metal-free click cycloaddition reactions and alternative cyclization methods. Synthesis. 2017;49:29-41. DOI: 10.1055/s-0036-1588904
  10. 10. Huisgen R. 1,3-Dipolar Cycloadditions. Proceedings of the Chemical Society. 1961:357. DOI: 10.1039/PS9610000357
  11. 11. Kolb HC, Finn MG, Sharpless KB. Click chemistry: Diverse chemical function from a few good reactions. Angewandte Chemie International Edition. 2001;40:2004-2021. DOI: 10.1002/1521-3773(20010601)40:11<2004::AID-ANIE2004>3.0.CO;2-5
  12. 12. Rostovtsev VV, Green LG, Fokin VV, Sharpless KB. Angewandte Chemie International Edition. 2002;41:2596-2599. DOI: 10.1002/1521-3773(20020715)41:14<2596::AID-ANIE2596>3.0.CO;2-4
  13. 13. Tornøe CW, Christensen C, Meldal M. Peptidotriazoles on solid phase: [1,2,3]-Triazoles by regiospecific copper (I)-catalyzed 1, 3-dipolar cycloadditions of terminal alkynes to azides. The Journal of Organic Chemistry. 2002;67:3057-3064. DOI: 10.1021/jo011148j
  14. 14. Wang Q, Chan TR, Hilgraf R, Fokin VV, Sharpless KB, Finn MG. Bioconjugation by copper (I)-catalyzed azide-alkyne [3+ 2] cycloaddition. Journal of the American Chemical Society. 2003;125:3192-3193. DOI: 10.1021/ja021381e
  15. 15. Wu P, Feldman AK, Nugent AK, Hawker CJ, Scheel A, Voit B, et al. Efficiency and fidelity in a click-chemistry route to triazole dendrimers by the copper (I)-catalyzed ligation of azides and alkynes. Angewandte Chemie International Edition. 2004;43:3928-3932. DOI: 10.1002/anie.200454078
  16. 16. Chan TR, Hilgraf R, Sharpless KB, Fokin VV. Polytriazoles as copper (I)-stabilizing ligands in catalysis. Organic Letters. 2004;6:2853-2855. DOI: 10.1021/ol0493094
  17. 17. Himo F, Lovell T, Hilgraf R, Rostovtsev VV, Noodleman L, Sharpless KB, et al. Copper (I)-catalyzed synthesis of azoles. DFT study predicts unprecedented reactivity and intermediates. Journal of the American Chemical Society. 2005;127:210-216. DOI: 10.1021/ja0471525
  18. 18. Zhang L, Chen X, Xue P, Sun HH, Williams ID, Sharpless KB, et al. Ruthenium-catalyzed cycloaddition of alkynes and organic azides. Journal of the American Chemical Society. 2005;127:15998-15999. DOI: 10.1021/ja054114s
  19. 19. McNulty J, Keskar K, Vemula R. The first well-defined silver (I)-complex-catalyzed cycloaddition of azides onto terminal alkynes at room temperature. Chemistry – A European Journal. 2011;17:14727-14730. DOI: 10.1002/chem.201103244
  20. 20. Morozova MA, Yusubov MS, Kratochvil B, Eigner V, Bondarev AA, Yoshimura A, et al. Regioselective Zn(OAc)2-catalyzed azide–alkyne cycloaddition in water: The green click-chemistry. Organic Chemistry Frontiers. 2017;4:978-985. DOI: 10.1039/C6QO00787B
  21. 21. Kim WG, Kang ME, Lee JB, Jeon MH, Lee S, Lee J, et al. Nickel-catalyzed azide–alkyne cycloaddition to access 1, 5-disubstituted 1,2,3-triazoles in air and water. Journal of the American Chemical Society. 2017;139:12121-12124. DOI: 10.1021/jacs.7b06338
  22. 22. Ding S, Jia G, Sun J. Iridium-catalyzed intermolecular azide–alkyne cycloaddition of internal thioalkynes under mild conditions. Angewandte Chemie International Edition. 2014;53:1877-1880. DOI: 10.1002/anie.201309855
  23. 23. Codelli JA, Baskin JM, Agard NJ, Bertozzi CR. Second-generation difluorinated cyclooctynes for copper-free click chemistry. Journal of the American Chemical Society. 2008;130:11486-11493. DOI: 10.1021/ja803086r
  24. 24. Ramachary DB, Ramakumar K, Narayana VV. Amino acid-catalyzed cascade [3+ 2]-cycloaddition/hydrolysis reactions based on the push–pull dienamine platform: Synthesis of highly functionalized NH-1,2,3-triazoles. Chemistry – A European Journal. 2008;14:9143-9147. DOI: 10.1002/chem.200801325
  25. 25. Danence LJT, Gao Y, Li M, Huang Y, Wang J. Organocatalytic enamide–azide cycloaddition reactions: Regiospecific synthesis of 1, 4, 5-trisubstituted-1,2,3-triazoles. Chemistry – A European Journal. 2011;17:3584-3587. DOI: 10.1002/chem.201002775
  26. 26. Belkheira M, El Abed D, Pons JM, Bressy C. Organocatalytic synthesis of 1,2,3-triazoles from unactivated ketones and arylazides. Chemistry – A European Journal. 2011;17:12917-12921. DOI: 10.1002/chem.201102046
  27. 27. Li W, Du Z, Huang J, Jia Q, Zhang K, Wang J. Direct access to 1,2,3-triazoles through organocatalytic 1, 3-dipolar cycloaddition reaction of allyl ketones with azides. Green Chemistry. 2014;16:3003-3006. DOI: 10.1039/C4GC00406J
  28. 28. Wan JP, Cao S, Liu Y. A metal-and azide-free multicomponent assembly toward regioselective construction of 1, 5-disubstituted 1,2,3-triazoles. The Journal of Organic Chemistry. 2015;80:9028-9033. DOI: 10.1021/acs.joc.5b01121
  29. 29. Kamalraj VR, Senthil S, Kannan P. One-pot synthesis and the fluorescent behavior of 4-acetyl-5-methyl-1,2,3-triazole regioisomers. Journal of Molecular Structure. 2008;892:210-215. DOI: 10.1016/j.molstruc.2008.05.028
  30. 30. Ramachary DB, Shashank AB, Karthik S. An organocatalytic azide–aldehyde [3+ 2] cycloaddition: High-yielding regioselective synthesis of 1, 4-disubstituted 1,2,3-triazoles. Angewandte Chemie International Edition. 2014;53:10420-10424. DOI: 10.1002/anie.201406721
  31. 31. Ali A, Corrêa AG, Alves D, Zukerman-Schpector J, Westermann B, Ferreira MA, et al. An efficient one-pot strategy for the highly regioselective metal-free synthesis of 1, 4-disubstituted-1,2,3-triazoles. Chemical Communications. 2014;50:11926-11929. DOI: 10.1039/C4CC04678A
  32. 32. Shashank AB, Karthik S, Madhavachary R, Ramachary DB. An enolate-mediated organocatalytic azide–ketone [3+ 2]-cycloaddition reaction: Regioselective high-yielding synthesis of fully decorated 1,2,3-triazoles. Chemistry – A European Journal. 2014;20:16877-16881. DOI: 10.1002/chem.201405501
  33. 33. Sakai K, Hida N, Kondo K. Reactions of α-polyhalo ketone tosylhydrazones with sulfide ion and primary amines. Cyclization to 1,2,3-thiadiazoles and 1,2,3-triazoles. Bulletin of the Chemical Society of Japan. 1986;59:179-183. DOI: 10.1246/bcsj.59.179
  34. 34. van Berkel SS, Brauch S, Gabriel L, Henze M, Stark S, Vasilev D, et al. Traceless tosylhydrazone-based triazole formation: A metal-free alternative to strain-promoted azide–alkyne cycloaddition. Angewandte Chemie International Edition. 2012;51:5343-5346. DOI: 10.1002/anie.201108850
  35. 35. Thomas J, John J, Parekh N, Dehaen W. A metal-free three-component reaction for the regioselective synthesis of 1, 4, 5-trisubstituted 1,2,3-triazoles. Angewandte Chemie International Edition. 2014;53:10155-10159. DOI: 10.1002/anie.201403453
  36. 36. Quan XJ, Ren ZH, Wang YY, Guan ZH. p-toluenesulfonic acid mediated 1, 3-dipolar cycloaddition of nitroolefins with NaN3 for synthesis of 4-aryl-NH-1,2,3-triazoles. Organic Letters. 2014;16:5728-5731. DOI: 10.1021/ol5027975
  37. 37. Kallander LS, Lu Q, Chen W, Tomaszek T, Yang G, Tew D, et al. 4-Aryl-1,2,3-triazole: A novel template for a reversible methionine aminopeptidase 2 inhibitor, optimized to inhibit angiogenesis in vivo. Journal of Medicinal Chemistry. 2005;48:5644-5647
  38. 38. Odlo K, Hentzen J, dit Chabert JF, Ducki S, Gani OA, Sylte I, et al. 1, 5-Disubstituted 1,2,3-triazoles as cis-restricted analogues of combretastatin A-4: Synthesis, molecular modeling and evaluation as cytotoxic agents and inhibitors of tubulin. Bioorganic & Medicinal Chemistry. 2008;16:4829-4838. DOI: 10.1016/j.bmc.2008.03.049
  39. 39. Yu JL, Wu QP, Zhang QS, Liu YH, Li YZ, Zhou ZM. Synthesis and antitumor activity of novel 2′, 3′-dideoxy-2′, 3′-diethanethionucleosides bearing 1,2,3-triazole residues. Bioorganic & Medicinal Chemistry Letters. 2010;20:240-243. DOI: 10.1016/j.bmcl.2009.10.127
  40. 40. Ashwini N, Garg M, Mohan CD, Fuchs JE, Rangappa S, Anusha S, et al. Synthesis of 1, 2-benzisoxazole tethered 1,2,3-triazoles that exhibit anticancer activity in acute myeloid leukemia cell lines by inhibiting histone deacetylases, and inducing p21 and tubulin acetylation. Bioorganic & Medicinal Chemistry. 2015;23:6157-6165. DOI: 10.1016/j.bmc.2015.07.069
  41. 41. Stefely JA, Palchaudhuri R, Miller PA, Peterson RJ, Moraski GC, Hergenrother PJ, et al. N-((1-benzyl-1 H-1,2,3-triazol-4-yl) methyl) arylamide as a new scaffold that provides rapid access to antimicrotubule agents: Synthesis and evaluation of antiproliferative activity against select cancer cell lines. Journal of Medicinal Chemistry. 2010;53:3389-3395. DOI: 10.1021/jm1000979
  42. 42. Yan SJ, Liu YJ, Chen YL, Liu L, Lin J. An efficient one-pot synthesis of heterocycle-fused 1,2,3-triazole derivatives as anti-cancer agents. Bioorganic & Medicinal Chemistry Letters. 2010;20:5225-5228. DOI: 10.1016/j.bmcl.2010.06.141
  43. 43. Majeed R, Sangwan PL, Chinthakindi PK, Khan I, Dangroo NA, Thota N, et al. Synthesis of 3-O-propargylated betulinic acid and its 1,2,3-triazoles as potential apoptotic agents. European Journal of Medicinal Chemistry. 2013;63:782-792. DOI: 10.1016/j.ejmech.2013.03.028
  44. 44. Kim TW, Yong Y, Shin SY, Jung H, Park KH, Lee YH, et al. Synthesis and biological evaluation of phenyl-1H-1,2,3-triazole derivatives as anti-inflammatory agents. Bioorganic Chemistry. 2015;59:1-11. DOI: 10.1016/j.bioorg.2015.01.003
  45. 45. Naaz F, Pallavi MP, Shafi S, Mulakayala N, Yar MS, Kumar HS. 1,2,3-triazole tethered indole-3-glyoxamide derivatives as multiple inhibitors of 5-LOX, COX-2 & tubulin: Their anti-proliferative & anti-inflammatory activity. Bioorganic Chemistry. 2018;81:1-20. DOI: 10.1016/j.bioorg.2018.07.029
  46. 46. Labadie GR, de la Iglesia A, Morbidoni HR. Targeting tuberculosis through a small focused library of 1,2,3-triazoles. Molecular Diversity. 2011;15:1017-1024. DOI: 10.1007/s11030-011-9319-0
  47. 47. Boechat N, Ferreira VF, Ferreira SB, Ferreira MLG, Silva FC, Bastos MM, et al. Novel 1,2,3-triazole derivatives for use against Mycobacterium tuberculosis H37Rv (ATCC 27294) strain. Journal of Medicinal Chemistry. 2011;54:5988-5999. DOI: 10.1021/jm2003624
  48. 48. Patpi SR, Pulipati L, Yogeeswari P, Sriram D, Jain N, Sridhar B, et al. Design, synthesis, and structure–activity correlations of novel dibenzo [b, d] furan, dibenzo [b, d] thiophene, and N-methylcarbazole clubbed 1,2,3-triazoles as potent inhibitors of mycobacterium tuberculosis. Journal of Medicinal Chemistry. 2012;55:3911-3922. DOI: 10.1021/jm300125e
  49. 49. Zhou B, He Y, Zhang X, Xu J, Luo Y, Wang Y, et al. Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents. Proceedings of the National Academy of Sciences. 2010;107:4573-4578. DOI: 10.1073/pnas.0909133107
  50. 50. Kant R, Kumar D, Agarwal D, Gupta RD, Tilak R, Awasthi SK, et al. Synthesis of newer 1,2,3-triazole linked chalcone and flavone hybrid compounds and evaluation of their antimicrobial and cytotoxic activities. European Journal of Medicinal Chemistry. 2016;113:34-49. DOI: 10.1016/j.ejmech.2016.02.041
  51. 51. Ruddarraju RR, Murugulla AC, Kotla R, Tirumalasetty MCB, Wudayagiri R, Donthabakthuni S, et al. Design, synthesis, anticancer, antimicrobial activities and molecular docking studies of theophylline containing acetylenes and theophylline containing 1,2,3-triazoles with variant nucleoside derivatives. European Journal of Medicinal Chemistry. 2016;123:379-396. DOI: 10.1016/j.ejmech.2016.07.024
  52. 52. Mady MF, Awad GE, Jørgensen KB. Ultrasound-assisted synthesis of novel 1,2,3-triazoles coupled diaryl sulfone moieties by the CuAAC reaction, and biological evaluation of them as antioxidant and antimicrobial agents. European Journal of Medicinal Chemistry. 2014;84:433-443. DOI: 10.1016/j.ejmech.2014.07.042
  53. 53. Lv JS, Peng XM, Kishore B, Zhou CH. 1,2,3-Triazole-derived naphthalimides as a novel type of potential antimicrobial agents: Synthesis, antimicrobial activity, interaction with calf thymus DNA and human serum albumin. Bioorganic & Medicinal Chemistry Letters. 2014;24:308-313. DOI: 10.1016/j.bmcl.2013.11.013
  54. 54. Kamal A, Hussaini SA, Sucharitha ML, Poornachandra Y, Sultana F, Kumar CG. Synthesis and antimicrobial potential of nitrofuran–triazole congeners. Organic & Biomolecular Chemistry. 2015;13:9388-9397. DOI: 10.1039/C5OB01353D
  55. 55. Maria de Lourdes GF, Pinheiro LC, Santos-Filho OA, Peçanha MD, Sacramento CQ, Machado V, et al. Design, synthesis, and antiviral activity of new 1H-1,2,3-triazole nucleoside ribavirin analogs. Medicinal Chemistry Research. 2014;23:1501-1511. DOI: 10.1007/s00044-013-0762-6
  56. 56. Krajczyk A, Kulinska K, Kulinski T, Hurst BL, Day CW, Smee DF, et al. Antivirally active ribavirin analogues–4, 5-disubstituted 1,2,3-triazole nucleosides: Biological evaluation against certain respiratory viruses and computational modelling. Antiviral Chemistry and Chemotherapy. 2014;23:161-171. DOI: 10.3851/IMP2564
  57. 57. Cheng H, Wan J, Lin MI, Liu Y, Lu X, Liu J, et al. Design, synthesis, and in vitro biological evaluation of 1 H-1,2,3-triazole-4-carboxamide derivatives as new anti-influenza A agents targeting virus nucleoprotein. Journal of Medicinal Chemistry. 2012;55:2144-2153. DOI: 10.1021/jm2013503

Written By

Abdul Aziz Ali

Submitted: 26 November 2019 Reviewed: 28 April 2020 Published: 13 October 2020