1,2,3 - triazole

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1,2,3-Triazole Table Of Contents 1.Introduction .................…………………….........[2-4] 2.Synthetic strategies of 1,2,3-triazoles …..........[5-8] 3.Anticancer Activity of 1,2,3-triazoles ……......[9-11] 4. Anti-inflammatory activity of 1,2,3-triazoles.[11-12] 5. Anti-tubercular activity of 1,2,3-triazoles ….[12-13] 6. Antiviral activity of 1,2,3-triazoles ..............[14-15] 7. Anti-bacterial activity of 1,2,3-triazoles ....... [16] 8. References ……………………………….……..[17-23]

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Page 1: 1,2,3 - Triazole

1,2,3-Triazole

Table Of Contents

1.Introduction .................…………………….........[2-4]

2.Synthetic strategies of 1,2,3-triazoles …..........[5-8]

3.Anticancer Activity of 1,2,3-triazoles ……......[9-11]

4. Anti-inflammatory activity of 1,2,3-triazoles.[11-12]

5. Anti-tubercular activity of 1,2,3-triazoles ….[12-13]

6. Antiviral activity of 1,2,3-triazoles .....….........[14-15]

7. Anti-bacterial activity of 1,2,3-triazoles ....... [16]

8. References ……………………………….……..[17-23]

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1,2,3-Triazole

◘ Abstract :

Triazole was first synthesized over a century ago, but still attracts attention of chemists,

biologists, technologists and other specialists , 1,2,3-Triazole is one of a pair of isomeric

chemical compounds with molecular formula C2H3N3, called triazoles, which have a

five-membered ring of two carbon atoms and three nitrogen atoms. 1,2,3-Triazole is a

basic aromatic heterocycle , Despite a significant work on 1, 2, 3-triazoles, continuous

efforts are still being made to identify novel heterocyclic compounds with potent

bioactivities , This research throws light on the detailed synthetic approaches which

have been used for the synthesis of triazoles since the early development in the area of

triazole chemistry. This has been followed by the in depth analysis of the triazoles with respect to their

medicinal significance.

♦ 1. Introduction

There are many heterocyclic ring structures, which have been designed [1] in such a way that their binding

efficiency with the receptor increases after structural modifications [2]. This medicinal chemistry is a boon

to the researchers and provides long-term advancement in the medical field [3]. One of the motif is triazoles,

which have been explored widely and still its scope is inevitable. Triazoles are heterocyclic organic

compounds containing five-membered ring with three nitrogen and two carbon atoms. Two isomeric forms

of triazoles are existed namely 1,2,3-triazole and 1,2,4-triazole [4]. Generally, 1,2,3-triazoles are further

subdivided into three main class, namely, monocyclic 1,2,3-triazoles, benzotriazoles and 1,2,3-triazolium

salts as depicted in Fig. 1.

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• Monocyclic 1,2,3-triazoles and benzotriazoles are remarkably stable

towards hydrolysis, oxidative/reductive conditions, and enzymatic

degradation but reductive cleavage occurs under forcing conditions

leading to the formation of triazolium salts [5,6].

• These motifs are effective amide surrogates in bioactive molecules

because of their strong dipole moments. Triazoles can also be used as a

linker and show bioisosteric effects on peptide linkage, aromatic ring,

double bonds and an imidazole ring. Some unique features like

hydrogen bond formation, dipole-dipole and π stacking interactions of

triazole compounds have increased their importance in the field of

medicinal chemistry as they bind with the biological target with high

affinity due to their improved solubility. In general, the molecular

specifications of the 1,4-disubstituted 1,2,3-triazoles are somewhat

similar to amide bonds in terms of distance and planarity clearly shown

in Fig. 2 [7–12].

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The 1,2,3-triazole based heterocycles have been well exploited

for the generation of many medicinal scaffolds exhibiting anti-

HIV, anticancer, antibacterial activities, etc.[13–18]. Numerous compounds bearing this moiety are also well

acknowledged for therapeutic effects elucidated in Fig. 3.

There are numerous amount of biologically active molecules containing 1,2,3-

triazole motif and were synthesized well before the ‘click chemistry’ approach

became popular. A few examples are shown in Fig. 3. The 1,2,3-triazole moiety

also serves as key synthetic intermediates in many industrial applications such as

agrochemicals [19–21], corrosion inhibitors [22,23], additives [24,25],

supramolecular chemistry [26,27], dendrimers, polymers [28–31], liquid crystals

[32–34], photostabilizers [35–37], pigments [38–41] and metal chelators [42–44].

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2. Synthetic strategies of 1,2,3-Triazoles

• 1,2,3-Triazole ring system has been a subject of intense research due to its versatile potential to interact with diverse biological systems. In recent

years, many synthetic methodologies have been developed for the synthesis of this ring system .

♦ Methods for the synthesis of 1, 2, 3-triazoles

Scheme 1

The most popular reaction that has been adapted to produce the 1, 2, 3-triazole moiety is the 1, 3-dipolar cycloaddition also known as Huisgen

cycloaddition, between an azide and a terminal alkyne. Although this reaction was discovered at the start of the 20th century, its detailed

mechanism was described by Huisgen in the 1960s [45]. This reaction is catalysed by the copper (I) metal and thus most often carried

out in the presence of copper (II) salts e.g. copper sulfate pentahydrate [46]

or copper acetate [47] using sodium ascorbate or metallic copper as a

reducing agent which reduces the copper (II) to copper (I). The solvent used

for this reaction contains a mixture of tert-butanol and water. By using this

solvent system the requirement of a base to generate copper acetylide

species is eliminated and the same can be used for the lipophilic compounds.

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Scheme 2

A palladium catalysed synthesis of 1, 2, 3-triazoles from alkenyl halides and

sodium azides added a new chapter in the Palladium chemistry [48].

Scheme 3

The terminal alkynes react with a mixture of benzyl or alkyl halides with

sodium azide in ethanol to produce 1, 4- disubstituted 1, 2, 3-triazoles in good yields [49]. It is catalysed by copper immobilized on 3-aminopropyl

functionalised silica gel.

Scheme 4

An efficient one pot synthesis of 1, 2, 3-triazole linked glycoconjugates involving 1, 3-dipolar cycloaddition in presence of Cu (I) as a catalyst has

been reported [50]. It is an easy method to prepare neoglycoconjugates

derived from unprotected saccharides or peracetylated saccharides.

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Scheme 5

Pankaja synthesized a family of closely related 1, 2, 3- triazoles as

anticonvulsant agents in which the dicarboximide moiety was lacking from

the triazole ring, unlike the traditional anticonvulsant agents [51].

Scheme 6

Terminal alkyne on reaction with iodobenzene and mixture of sodium azide,

cuprous iodide and sodium ascorbate gives 1, 2, 3-triazole [52].

Scheme 7

Primary aliphatic amines undergo diazo transfer to form azides which are

converted into 1, 2, 3-triazoles under appropriate reaction conditions [53].

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Scheme 8

Non-fluorescent 3-azide coumarins can be converted into fluorogenic probes

by reacting them with alkynes. This method is used to generate fluorescent

DNA probes used in the molecular biology [54].

Scheme 9

The organic azides undergo cycloaddition with immobilized alkynes on

polystyrene resins resulting in the formation of 1, 2, 3-triazoles [55].

Scheme 10

Condensed 1, 2, 3-triazoles can be synthesized by the oxidation of arylazo

heterocycles having an amino group in the ortho position [56].

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3. Anticancer Activity of 1,2,3 Triazoles

The discovery of new drugs for cancer therapy is one of the medicinal chemistry’s most investigated areas because the global prevalence of this disease continues to grow. The greatest

challenge for scientists in this area is to develop new drugs that are more effective and have lower toxicity. Selectivity is the dilemma in cancer therapy for the achievement of drug delivery to a localized tumor and for an even

distribution throughout the body, including the tumor tissues. Other challenges in the treatment of cancer using chemotherapy include drugs with short half-lives in blood circulation, fewer side

effects, and effectiveness. The development of research in this area aims to attack the problem from different angles, such as chemotherapy conjugated with drug carriers to act as magic bullets

or to enhance distribution of the drug molecule in the body [57].

Recently, several triazoles have been found to have activities against several cancer cell lines [58, 59]. The researchers are focusing their efforts on the anticancer activity [60–61] in compound

hybrids of 1,2,3-1H-triazole tethered with the β-lactam (115), triterpenoid (116), and chalcone (117, 118) moieties that were evaluated against several cancer cell lines and were selective to A-

549(lung) [62], chalcone-pyrrolo[2,1-c] [1,4]benzodiazepine conjugates containing alkane spacers with promising in vitro anticancer activity in concentrations ranging from <0.1–2.92 μM [63]. These

compounds have also been screened on the apoptosis enzymes that regulate cellular programmed cell death of unnecessary cells as shown in Fig. A [64, 65].

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• Drugs used therapeutically for other diseases can serve as models in the search for new lead compounds.

Revankar and coworkers synthesized a series of six analogues of the antiviral drug ribavirin (121–126)

containing 1,2,3-2H-triazoles and studied them as inhibitors of the tumor cell line HL-60 [66]. The

derivatives were obtained by a synthetic sequence (Scheme 11) that begins with a condensation

reaction between the triazole compound (119) and ribofuranoside (120) catalyzed.

Page 11: 1,2,3 - Triazole

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by a Lewis acid, trimethylsilyl triflate. The product 121 is then converted by several reactions to the

nucleosides 122–126. 126 inhibited HL-60 at a level that was 50% of the inhibitory effect of ribavirin

(Scheme B).

Metal complexes are widely used in chemistry and in many treatments of diseases, including cancer

chemotherapy. For example, organotin (IV) carboxylates are used in many applications in chemistry and

biology, such as antitumor activity [67].

Tiam and coworkers synthesized three triorganotin 2-phenyl-1,2,3-triazole-4-carboxylates (127a–c), and a

bioassay showed that these compounds have good antitumor activity against three human tumor cell lines

(HeLa, CoLo205, and MCF-7) [68]. In addition, platinum complexes are widely used in cancer

chemotherapy. For example, cisplatin, approved by the FDA in 1978, and carboplatin [69], are the most

commonly used anticancer platinum complexes in the clinical treatment of testicular and ovarian malignant

tumors [70–72], and their mechanism of action is the induction of apoptosis [73, 74].

Considering these findings, Reedijk and coworkers [75] synthesized two binuclear platinum complexes [76]

with triazoles as ligands. The compounds 130 and 131 demonstrated to have better anticancer activity (18

times more cytotoxic)

than cisplatin against tumor cell lines (acute lymphoblastic leukemia cisplatin sensitive and cisplatin-

resistant) (Fig. A).

Girard and coworkers [77, 78] synthesized mono- and bis-1,2,3-triazoles from bis-alkynes to be tested

against the human tumor strain B16 (murine melanoma cell line) that is highly malignant, metastatic, and

chemoresistant [79–81].

4. Anti-inflammatory activity of 1,2,3-triazoles

• Haider et al have synthesized a library of benzoxazolinone based 1, 2, 3-triazoles using

click chemistry approach and screened them for their in vitro and in vivo anti-inflammatory

activity. The compound 1 exhibited potent in vivo anti-inflammatory activity ,The compound 2 exhibited significant TNF-α inhibitory activity [82].

• Shafi et al have synthesized novel bis-heterocycles encompassing 2-mercapto benzothiazole

and 1, 2, 3- triazoles and evaluated them for their anti-inflammatory activity by using biochemical cyclooxygenase (COX) activity assays [83].

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• Assis et al have synthesized 1, 2, 3-triazole based phthalimide

derivatives by the 1,3-dipolar cycloaddition reaction of N-(azido-

alkyl)phthalimides with terminal alkynes and screened them for their

anti-inflammatory activity.[84]

• Silva et al carried out the synthesis and anti-inflammatory activity of novel

glucosyl triazoles from a reaction of 2, 3, 4, 6-tetra-O-acetyl-β-D-glucopyranosyl

azide and terminal alkynes using ultrasound energy. The compound 5 exhibited

potent anti-inflammatory activity [85]

5. Anti-tubercular activity of 1,2,3-triazoles

• Somu et al carried out the synthesis of the compound 6 which was found to be

the inhibitor of Mycobacterium tuberculosis. Its activity is due to the inhibition of

the adenylate forming enzyme MbtA, which is involved in biosynthesis of the

mycobactins.[86]

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• Yempala et al have synthesized a series of novel dibenzofuran based 1, 2, 3-

triazole derivatives using click chemistry approach and screened them for their

in vitro anti-mycobacterial activity against Mycobacterium tuberculosis H37Rv.

The compound 7 was found to be most potent antitubercular agent with lowest

cytotoxicity against the HEK-293T cell line.[87]

• Menendez et al have synthesized a series of 1,2,3- triazoles as inhibitors of

Mycobacterium tuberculosis H37Rv. Compounds 8 and 9 were found to be good

inhibitors of Mycobacterium tuberculosis.[88]

• Menendez et al have synthesized and screened the phenethyl based 1, 2, 3-

triazoles as the inhibitors of Mycobacterium tuberculosis H37Rv. The compound

10 was found to exhibit a potent antitubercular activity.[89]

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6. Antiviral activity of 1,2,3-triazoles

• Piotrowska et al have reported the synthesis and the antiviral activity of novel

isoxazolidine nucleotide analogues with a 1, 2, 3-triazole linker.

The synthesized 1, 2, 3-triazole based isoxazolidine phosphonates were evaluated

for their in vitro activity against a variety of DNA and RNA viruses.[90]

• He et al have carried out the synthesis of novel 1, 2, 3- triazole-containing

derivatives of rupestonic acid and screened them for their antiviral activity

against influenza virus using oseltamivir and ribavirin as the standard drug.[91]

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• Jorda˜o et al have synthesized N-amino-1,2,3-triazole derivatives i.e. 1-(4-

substituted-phenylamino)-5-methyl- 1H-[1,2,3]-triazole-4-carboxylic acid

hydrazides and 1- (substitutedphenylamino)-5-methyl-1H-[1,2,3]-triazole-4-

carboxylic acid ethyl esters and screened them against Cantagalo virus

replication. This compound exhibited an inhibition of 55.70% on the virus

progeny production.[92]

• Silva et al have carried out the synthesis and the in vitro HIV-RT inhibitory

activity of 1-benzyl-1H-1, 2, 3-triazole derivatives of carbohydrates (compound A

and B ) .[93]

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7. Anti-bacterial activity of 1,2,3-triazoles

• Phillips et al have synthesized novel 5-(4-methyl-1, 2, 3- triazole)methyl

oxazolidinones and screened them for their in vitro antibacterial activity against

the Gram-positive and Gram-negative bacteria using linezolid and vancomycin

as standard.[94]

• Wang et al have synthesized sulfanilamide based 1, 2, 3- triazoles and screened

them for their in vitro antibacterial (S. aureus, B. subtilis, E. coli, P. aeruginosa)

and antifungal (C. albicans and C. mycoderma) activities.[95]

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