Triazoles: Synthesis and Applications

*Azoles - Synthesis, Properties, Applications and Perspectives*

thiazole derivatives as potential anticancer agents. Scientia

[158] Kryshchyshyn A, Roman O, Lozynskyi A, Lesyk R. Thiopyrano[2,3-d] thiazoles as new efficient scaffolds in medicinal chemistry. Scientia Pharmaceutica. 2018;**86**(2):26. DOI:

10.3390/scipharm86020026

Pharmaceutica. 2012;**80**(3):509-530. DOI: 10.3797/scipharm.1204-02

[159] Atamanyuk D, Zimenkovsky B, Atamanyuk V, Nektegayev I, Lesyk R. Synthesis and biological activity of new thiopyrano[2,3-d]thiazoles containing a naphthoquinone moiety. Scientia Pharmaceutica. 2013;**81**(2):423-436. DOI: 10.3797/scipharm.1301-13

[160] Atamanyuk D, Zimenkovsky B,

Communications. 2013;**44**(2):237-244. DOI: 10.1080/00397911.2013.800552

Synthesis and antitrypanosomal activity

[162] Kryshchyshyn A, Kaminskyy D, Nektegayev I, Grellier P, Lesyk R. Isothiochromenothiazoles—A class of fused thiazolidinone derivatives with established anticancer activity that inhibits growth of *Trypanosoma brucei brucei*. Scientia Pharmaceutica.

[161] Zelisko N, Atamanyuk D, Vasylenko O, Grellier P, Lesyk R.

of new 6,6,7-trisubstituted thiopyrano[2,3-d][1,3]thiazoles. Bioorganic and Medicinal Chemistry Letters. 2012;**22**(23):7071-7074. DOI:

10.1016/j.bmcl.2012.09.091

2018;**86**(4):47. DOI: 10.3390/

scipharm86040047

5-Ethoxymethylidene-4-thioxo-2 thiazolidinone as versatile building block for novel biorelevant small molecules with thiopyrano[2,3-d] [1,3]thiazole core. Synthetic

Atamanyuk V, Lesyk R.

thiosemicarbazones, aminoacylthiosemicarbazides and acylthiazolidones against *Trypanosoma cruzi*. Bioorganic & Medicinal

10.1016/j.bmc.2006.01.034

ejps.2003.10.011

Chemistry. 2006;**14**(11):3749-3757. DOI:

[152] Seebacher W, Brun R, Weis R. New 4-aminobicyclo[2.2.2]octane derivatives and their activities against plasmodium falciparum and Trypanosoma b. rhodesiense. European Journal of Pharmaceutical Sciences. 2004;**21**(2-3):225-233. DOI: 10.1016/j.

[153] da Silva E, Oliveira e Silva D, Oliveira A, da Silva Mendes C, dos Santos T, da Silva A, et al. Design and synthesis of potent anti-*Trypanosoma cruzi* agents new thiazoles derivatives which induce apoptotic parasite death. European Journal of Medicinal Chemistry. 2017;**130**:39-50. DOI: 10.1016/j.ejmech.2017.02.026

[154] Caputto M, Ciccarelli A, Frank F, Moglioni A, Moltrasio G, Vega D, et al. Synthesis and biological evaluation of some novel 1-indanone thiazolylhydrazone derivatives as anti-*Trypanosoma cruzi* agents. European Journal of Medicinal Chemistry. 2012;**55**:155-163. DOI: 10.1016/j.

[155] Kryshchyshyn A, Kaminskyy D, Karpenko O, Gzella A, Grellier P, Lesyk R. Thiazolidinone/thiazole based hybrids—New class of antitrypanosomal agents. European Journal of Medicinal Chemistry. 2019;**174**:292-308. DOI: 10.1016/j.

[156] Lesyk R, Kaminskyy D, Vasylenko O, Atamanyuk D, Gzella A. Isorhodanine

synthesis of fused thiopyrano[2,3-d][1,3] thiazoles. Synlett. 2011;**10**:1385-1388.

[157] Kryshchyshyn A, Atamanyuk D, Lesyk R. Fused thiopyrano[2,3-d]

and thiorhodanine motifs in the

DOI: 10.1055/s-0030-1260765

ejmech.2012.07.013

ejmech.2019.04.052

**62**

**Chapter 4**

**Abstract**

drug discovery

**1. Introduction**

β-lactum antibiotic tazobactam, etc. [8].

**2. Synthesis of 1,2,3-triazoles**

**65**

*Abdul Aziz Ali*

1,2,3-Triazoles: Synthesis

and Biological Application

activities of this promising heterocycle will also be discussed.

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

**Keywords:** 1,2,3-triazoles, click chemistry, organocatalysis, biological activity,

Nitrogen-containing heterocyclic compounds are indispensable for life as they

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]:

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 [1–6]. 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

#### **Chapter 4**

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

*Abdul Aziz Ali*

#### **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 [1–6]. 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].

#### **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]:


#### **2.1 Huisgen 1,3-dipolar cycloaddition**

Huisgen 1,3-dipolar cycloaddition was the most straightforward and atomeconomical 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].

*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 coppercatalyzed 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

In 2005, Fokin and coworkers devised an efficient approach for the construction

The McNulty group reported a well-defined Ag(I) complex for the regioselective

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].

synthesis of 1,4-disubstituted 1,2,3-triazoles at room temperature [19].

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

mild reaction conditions [14–17].

*1,2,3-Triazoles: Synthesis and Biological Application DOI: http://dx.doi.org/10.5772/intechopen.92692*

substituted 1,2,3-triazoles [18].

**67**

#### **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*

*1,2,3-Triazoles: Synthesis and Biological Application DOI: http://dx.doi.org/10.5772/intechopen.92692*

i. Huisgen 1,3-dipolar cycloaddition

*Azoles - Synthesis, Properties, Applications and Perspectives*

ii. Metal-catalyzed 1,3-dipolar cycloaddition

iii. Strain-promoted azide alkyne cycloaddition

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

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*

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

**2.2 Metal-catalyzed 1,3-dipolar cycloaddition**

**2.1 Huisgen 1,3-dipolar cycloaddition**

unsatisfactory [10].

**Figure 1.**

**66**

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

*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 coppercatalyzed 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 [14–17].

$$\begin{array}{ccccc} \text{R}^{\bullet}\text{-}\text{N}\_{3} & \begin{array}{c} \text{CuSO}\_{4}\text{-}5\text{H}\_{2}\text{O} \text{ (1 mol\%} \text{ } \text{)} \\ \text{Sodium}\text{-}\text{(2 mol\%)} \text{ } \text{H}^{\bullet}\text{-}\text{(2 mol\%)} \\ \text{H}^{\bullet}\text{-} \text{O} \\ \text{H}^{\bullet}\text{-} \text{O} \text{ } \text{H}^{\bullet}\text{-} \\ \text{N}^{\bullet} \text{-} \text{N}^{\bullet} \\ \text{H}^{\bullet}\text{-} \text{N}\_{2} & \begin{array}{c} \text{Cl}^{\bullet}\text{-} \text{(2 mol\%)} \\ \text{H}^{\bullet}\text{-} \text{(2 mol\%)} \\ \text{H}^{\bullet}\text{-} \text{(2 mol\%)} \\ \text{H}^{\bullet}\text{-} \text{(2 mol\%)} \\ \text{H}^{\bullet}\text{-} \text{(2 mol\%)} \\ \text{H}^{\bullet}\text{-} \text{(2 mol\%)} \\ \end{array} & \begin{array}{c} \text{R}^{\bullet}\text{-} \text{(2 mol\%)} \\ \text{R}^{\bullet}\text{-} \text{(2 mol\%)} \\ \text{R}^{\bullet}\text{-} \text{(2 mol\%)} \\ \text{R}^{\bullet}\text{-} \text{(2 mol\%)} \\ \text{R}^{\bullet}\text{-} \text{(2 mol\%)} \\ \end{array} \end{array}$$

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].

$$\mathsf{R}^{\mathsf{L}\rightarrow\mathsf{N}\_{3}} + \begin{array}{c} \mathsf{R} \\ \begin{array}{c} \mathsf{C}\mathsf{b}^{\mathsf{L}\texttt{R}\texttt{c}\texttt{C}\texttt{c}\texttt{c}\texttt{R}\texttt{c}\texttt{c}\texttt{c}\texttt{c}\texttt{c}\texttt{c}\texttt{c}\texttt{N} \\ \hline \end{array} \end{array} \begin{array}{c} \mathsf{R} \\ \begin{array}{c} \mathsf{C}\mathsf{b}\texttt{c}\texttt{a}\texttt{a}\texttt{c}\texttt{c}\texttt{c}\texttt{c}\texttt{c}\texttt{c}\texttt{c}\texttt{c}\texttt{c}\texttt{N} \\ \hline \end{array} \end{array} \begin{array}{c} \mathsf{R} \\ \begin{array}{c} \mathsf{N}\_{\mathsf{N}\_{3}} \\ \mathsf{N}\_{\mathsf{N}\_{3}} \\ \mathsf{N}\_{\mathsf{N}\_{3}} \\ \mathsf{N}\_{\mathsf{N}\_{3}} \\ \end{array} \end{array}$$

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].

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].

*1,2,3-Triazoles: Synthesis and Biological Application DOI: http://dx.doi.org/10.5772/intechopen.92692*

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

Iodine mediated, oxidant free synthesis of 1,5-disubstituted 1,2,3-triazoles

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

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

was reported by the Wan group using primary amines, enamines and

allyl ketones [27].

tosylhydrazine [28].

azides [29].

addition reaction [30].

**69**

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].

*1,2,3-Triazoles: Synthesis and Biological Application DOI: http://dx.doi.org/10.5772/intechopen.92692*

In 2017, Kim et al. devised Cp2Ni/Xantphos catalytic method to access

Sun and coworkers reported intermolecular iridium-catalyzed azide-alkyne

Despite the overwhelming popularity of click chemistry in modern science

system due to cellular toxicity. The Bertozzi group explored an interesting proto-

Organocatalytic reactions has gained considerable attention in the synthesis of 1,2,3-triazoles using enamines, enolates as dipolarophiles. Besides, activated alkenes

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

and technology, the using of metals creates serious concern in biological

col 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

cycloaddition reaction (IrAAC) of electron-rich internal alkynes [22].

1,5-disubstituted 1,2,3-triazoles under mild condition [21].

*Azoles - Synthesis, Properties, Applications and Perspectives*

**2.3 Strain-promoted azide alkyne cycloaddition**

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

were established as a useful substrate for triazole formation.

any catalyst [23].

**68**

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].

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

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

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 com-

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 contrib-

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

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

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 antiproli-

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

pounds with different modes of actions has received significant interest.

with β-tubulin via H-bonding with numerous amino acids [38].

ferative agent with an IC50 of 2 μM against MV4-11 cells [40].

with sodium azide [36].

blocks in drug discovery.

**3.1 Anti-cancer activity**

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

*1,2,3-Triazoles: Synthesis and Biological Application DOI: http://dx.doi.org/10.5772/intechopen.92692*

ute in binding to the active site of enzyme [37].

compared to the control drug floxuridine [39].

human breast tumor cells [41].

**71**

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

$$\underset{\mathbf{R}\sim\mathbb{N}^{3}}{\operatorname{\hspace{1cm}}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{1cm}}\text{\hspace{$$

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].

#### **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**

Paixão et al. reported the use of alkylidenemalononitriles in 1,3-dipolar

In their another pioneering work, Ramachary and coworkers reported an interesting organocatalytic [3 + 2]-cycloaddition reaction of ketones with azides for

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

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].

cycloaddition with aromatic azides mediated by DBU [31].

*Azoles - Synthesis, Properties, Applications and Perspectives*

synthesis of fully substituted 1,2,3-triazoles [32].

1,2,3-triazoles [33].

**70**

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 2 μM 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].

#### *Azoles - Synthesis, Properties, Applications and Perspectives*

Lin and coworkers synthesized a series of heterocycle-fused 1,2,3-triazoles and evaluated their cytotoxic activity. With IC50 values lower than 1*:*9 μg*=*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*:*5 μM, respectively) against leukemia cell line HL-60 (5–7-fold higher potency than betulinic acid) [43].

#### **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

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

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 (IC50 0*:*12 µM) with good COX-2 selectivity index (COX-2/COX-1) of 0.058 and 0.046, respectively

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

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 tubercu-*

1,2,3-triazole-4-yl)methylene] isonicotinoyl hydrazides, **13** revealed significant activity with minimum inhibitory concentration (MIC) value of 0*:*62 μg*=*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

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].


*losis* strain H37Rv (ATCC 27294). Derivatives of isoniazid, (E)-N<sup>0</sup>

against *M. tuberculosis* strain H37Rv exhibited MIC ¼ 0*:*78 μg*=*mL [48].

prompted medicinal chemists to develop alternative scaffolds.

*1,2,3-Triazoles: Synthesis and Biological Application DOI: http://dx.doi.org/10.5772/intechopen.92692*

(**Figure 3**) [45].

**73**

**Figure 4.**

**3.3 Antitubercular activity**

candidates has received enormous interest.

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

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

*1,2,3-Triazoles: Synthesis and Biological Application DOI: http://dx.doi.org/10.5772/intechopen.92692*

**Figure 4.**

Lin and coworkers synthesized a series of heterocycle-fused 1,2,3-triazoles and evaluated their cytotoxic activity. With IC50 values lower than 1*:*9 μg*=*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

1,2,3-triazole derivatives of betulinic acid were synthesized by Koul et al. and

Inflammation is particularly complex biological process of body tissues, where

membrane-bound phospholipids release arachidonic acid (AA), followed by

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

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

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*:*5 μM, respectively) against leukemia cell line HL-60 (5–7-fold higher potency than

*Azoles - Synthesis, Properties, Applications and Perspectives*

derivative [42].

betulinic acid) [43].

**Figure 3.**

**72**

**Figure 2.**

**3.2 Anti-inflammatory activity**

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

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 (IC50 0*:*12 µM) with good COX-2 selectivity index (COX-2/COX-1) of 0.058 and 0.046, respectively (**Figure 3**) [45].

#### **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<sup>0</sup> -[(1-aryl)-1H-1,2,3-triazole-4-yl)methylene] isonicotinoyl hydrazides, **13** revealed significant activity with minimum inhibitory concentration (MIC) value of 0*:*62 μg*=*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 ¼ 0*:*78 μg*=*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].

#### **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].

and antifungal activity (MIC ¼ 3*:*9 μg*=*mL) compared to the standard miconazole (MIC ¼ 7*:*8 μg*=*mL) against *C. albicans* and *C. parapsilosis* (**Figure 5**) [54].

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

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),

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

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

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.

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

and H5N1), influenza B, measles and respiratory syncytial viruses [56].

IC50 values ranging from 0.5 to 4.6 μM (**Figure 6**) [57].

**3.5 Antiviral activity**

**Figure 6.**

respectively [55].

**4. Conclusion**

**Acknowledgements**

**Conflict of interest**

**75**

There are no conflicts to declare.

antiviral agents is of significant interest.

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

*1,2,3-Triazoles: Synthesis and Biological Application DOI: http://dx.doi.org/10.5772/intechopen.92692*

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 25 μg*=*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*:*9 μg*=*mL against different bacterial strains)

**Figure 5.** *Representative examples of 1,2,3-triazole containing molecules with antimicrobial activity.* *1,2,3-Triazoles: Synthesis and Biological Application DOI: http://dx.doi.org/10.5772/intechopen.92692*

**Figure 6.**

**3.4 Antimicrobial activity**

antibacterial activity [50].

**Figure 5.**

**74**

Fungal and bacterial infections create severe apprehension for human and animal survival. The inefficacy of available drugs and rising resistant strains demand

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

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

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 25 μg*=*mL [52]. Zhou et al. reported a series of 1,2,3-triazole-derived naphthalimides for poten-

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*:*9 μg*=*mL against different bacterial strains)

tial antimicrobial activity. Bioactive assay revealed that **21** showed better anti-*Escherichia coli* activity than existing drugs Norfloxacin and Chloromycin [53].

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

significant interest into new classes of antimicrobial agents.

*Azoles - Synthesis, Properties, Applications and Perspectives*

against *S. aureus, B. cereus* and *Escherichia coli*, respectively [51].

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

and antifungal activity (MIC ¼ 3*:*9 μg*=*mL) compared to the standard miconazole (MIC ¼ 7*:*8 μg*=*mL) against *C. albicans* and *C. parapsilosis* (**Figure 5**) [54].

#### **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].

#### **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.

#### **Acknowledgements**

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

#### **Conflict of interest**

There are no conflicts to declare.

*Azoles - Synthesis, Properties, Applications and Perspectives*

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### **Author details**

Abdul Aziz Ali Material Science and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat, Assam, India

\*Address all correspondence to: aaziz496@gmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*1,2,3-Triazoles: Synthesis and Biological Application DOI: http://dx.doi.org/10.5772/intechopen.92692*

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**Author details**

Abdul Aziz Ali

**76**

and Technology, Jorhat, Assam, India

provided the original work is properly cited.

\*Address all correspondence to: aaziz496@gmail.com

*Azoles - Synthesis, Properties, Applications and Perspectives*

Material Science and Technology Division, CSIR-North East Institute of Science

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

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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

activity in acute myeloid leukemia cell lines by inhibiting histone deacetylases,

*Azoles - Synthesis, Properties, Applications and Perspectives*

[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-

Medicinal Chemistry. 2011;**54**: 5988-5999. DOI: 10.1021/jm2003624

[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

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mycobacterium tuberculosis. Journal of

[49] Zhou B, He Y, Zhang X, Xu J, Luo Y,

Medicinal Chemistry. 2012;**55**: 3911-3922. DOI: 10.1021/jm300125e

mycobacterium protein tyrosine phosphatase B for antituberculosis agents. Proceedings of the National Academy of Sciences. 2010;**107**: 4573-4578. DOI: 10.1073/

[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;

[51] Ruddarraju RR, Murugulla AC, Kotla R, Tirumalasetty MCB,

Design, synthesis, anticancer,

Wudayagiri R, Donthabakthuni S, et al.

antimicrobial activities and molecular docking studies of theophylline

containing acetylenes and theophylline

**113**:34-49. DOI: 10.1016/j. ejmech.2016.02.041

Wang Y, et al. Targeting

pnas.0909133107

9319-0

and inducing p21 and tubulin acetylation. Bioorganic & Medicinal Chemistry. 2015;**23**:6157-6165. DOI:

10.1016/j.bmc.2015.07.069

10.1021/jm1000979

[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:

[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] Majeed R, Sangwan PL,

Chinthakindi PK, Khan I, Dangroo NA, Thota N, et al. Synthesis of 3-Opropargylated 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] 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 antiinflammatory agents. Bioorganic

Chemistry. 2015;**59**:1-11. DOI: 10.1016/j.

[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 & antiinflammatory activity. Bioorganic Chemistry. 2018;**81**:1-20. DOI: 10.1016/

bioorg.2015.01.003

j.bioorg.2018.07.029

**80**

[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] 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] 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] 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] 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] 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

Section 4

Miscellaneous Applications

of Azoles

**83**

Section 4
