Asif & al. / Mor. J. Chem.

2 N°3 (2014) 136-164

A brief study of various synthetic methods of triazoles derivatives

and their biological potential

Mohammad Asif

Department of Pharmacy, GRD(PG)IMT, Dehradun, (UK), 248009, India

* Corresponding author: aasif321@gmail.com

Received 09 June 2014, Revised 16 July 2014, Accepted 17 July 2014.

Abstract
In the last few years, heterocyclic compounds have attracted strong interest and a lot of
work has been done on triazole ring. Many different derivatives have been prepared from it
which possesses useful pharmacological activities. Different pharmacological activities of
triazole ring and its derivatives possess a wide range of pharmacological activities such as
anticancer, anticonvulsant, antimicrobial, anti-inflammatory, antioxidant, antitubercular,
antimalarial, antinociceptive etc. In triazole ring, substitution at 1,4 and 1,3 positions of a
more electronegative group will possess more active analogues. Various pharmacological
activities of triazole in one place and it is also the milestone for the new research towards
this moiety. The triazole moiety has attracted the attention of many researchers to explore
this skeleton to its multiple potential against several activities. A literature survey of
procedures for the preparation of 1,2,4-triazole and 1,2,3-triazoles is presented by
generalized synthetic method.

Key words: Heterocyclic, Biological activities, triazole, synthesis.

Introduction
The chemistry of N-bridged heterocycles derived from 1,2,4-triazole has received considerable
attention in recent year due to their usefulness in different areas of biological activities and as
industrial intermediates. 1,2,4-triazole moiety appears frequently in the structure of various
natural products1 and the synthesis of compounds incorporating this moiety has attracted
widespread attention of chemists as well as biologists, mainly due to their diverse biological
activities in pharmaceutical and agrochemical fields. Triazoles are the class of heterocyclic
compounds [1] which are under study since many a years. 1,2,4-Triazole is one of a pair of

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isomeric chemical compounds with molecular formula C2H3N3, called triazoles, which have a
five-membered ring of two carbon atoms and three nitrogen atoms azole ring are readily able to
bind with a variety of enzymes and receptors in biological system via diverse non-covalent
interactions, and thus display versatile biological activities. In recent years, the chemistry of
triazoles and their fused heterocyclic derivatives has received considerable attention owing to
their synthetic and effective biological importance. The derivatization of Triazole is considered
to be based on the phenomenon of bioisosterism in which replacement of oxygen of oxadiazole
nucleus with nitrogen atom yields triazole analogue. There are two possible isomers of triazole
(A and B) depending on the position of nitrogen atom in the ring and are numbered as shown in
Fig. 1. Out of the two triazoles, 1,2,4-triazole have drawn great attention to medicinal chemists
from two decades due to its wide variety of activity [2], low toxicity and good Pharmacokinetic
and Pharmacodynamic profiles (Saini and Dwivedi. 2013). Its diversity in showing the
pharmacological activities is mind blowingly identified well by the medicinal chemists as;
Pyrimidines [3], D‐manno‐pentitol‐1‐yl‐1,2,4‐triazoles [4], benzotriazoles [5], indoles [6],
quinolones [7], triazolo thymidines [8], are in record. Literature survey reveals that 1,2,4-triazole
derivatives exhibit wide range of biological activities including antibacterial [9-11] antifungal
[12,13] antitumour [14], analgesic, anti-inflammatory [15], antitubercular [16], anti-convulsant
[17], anticancer [18], antimalarial [19], antiviral [20], analgesic [21] and antimigrain [22] CNS
stimulants, sedatives, antianxiety activities. Now a day’s research is concentrated towards the
introduction of new and safe therapeutic agents of clinical importance. The triazoles are said to
be the isosters of imidazoles in which the carbon atom of imidazole is isosterically replaced by
nitrogen. Triazoles nucleus have been incorporated into a wide variety of therapeutically
interesting drug candidates. They are used as optical brightening agents, as antioxidants, as
corrosion inhibitors and as additives with a variety of other functions. Many dye stuffs and
pigments have heterocyclic. The Triazole derivative possess a wide a range of pharmacological
activities. The importance of triazole derivatives lies in the field that these have good position in
heterocyclic chemistry, due to its various biological activities [23].

H
N N N
N N
H N
1, 2, 4 triazole (A) 1,2,3 triazole (B)

Figure 1: Triazoles

Other heterocyclic moiety with triazole ring: Schiff bases are considered as a very important
class of organic compounds which have wide applications in many biological aspects [24] Many

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Schiff bases containing 1,2,4-triazole moiety exhibit antibacterial, antifungal [25] and
antitumoral activities [26] The substituted nicotinic acid is among the various heterocycles that
have received most attention during last three decades as potential biomolecules. Nicotinic acid
derivatives exhibit antibacterial, antioxidant, anti-inflammatory and anticarcinogenic activities. It
is seen from the current literature that pyridine congeners are associated with different biological
properties like pesticidal [27,28], insecticidal and antifungal activities. A large number of
antibiotics contain amide linkage. Several derivatives of amides were prepared and found to
possess antimicrobial activities. Literature survey reveals that various drugs e.g. penicillin
(antibacterial), pyrazinamide (antitubercular), indinavir, ritonavir. (Protease inhibitors as anti-
AIDS) etc contain their particular activities due to the amide linkage present in their structure.
Chemistry: Triazole, also known as pyrrodiazole is one of the classes of organic heterocyclic
compounds containing a fivemembered diunsaturated ring structure composed of three nitrogen
atoms and two carbon atoms at non-adjacent positions. The simplest form of the triazole family
is triazole itself. Triazole is a white to pale yellow crystalline solid with a weak, characteristic
odour; it is soluble in water and alcohol, melts at 120°C and boils at 260°C. It occurs as a pair of
isomeric chemical compounds 1,2,3-triazole, and 1,2,4-triazole, with molecular formula C2H3N3,
and a molecular weight of 69.06 . The two isomers are 1,2,3 and 1,2,4-triazole [29,30].

Table-1. Chemical characteristics of 1,2,3 and 1,2,4-triazole

Properties of 1, 2, 3-triazole Properties of 1, 2, 4-triazole
Molecular formula C2H3N3 Molecular formula- C2H3N3
Molar mass 69.0654 Molar mass - 69.0654
Boiling point 203 °C Boiling point- 260
Melting point 23-25 °C Melting point - 120-121°C
Density 1.192 g/cm-3 Density - 1.394 g/cm-3
Appearance colourless liquid Appearance white solid
Solubility in water very soluble Solubility in water very soluble
Basicity (pKb) 9.4 Basicity -(pKb) 10.3
Acidity (pKa) 1.2 Acidity -(pKa) 2.2
Vapour Pressure 0.4 mmhg (25oc) Vapour Pressure 0.02 mmhg (25oc)

Biological profile of triazole derivatives: Triazole refers to either one of a pair of isomeric
chemical compounds, having a five membered ring of two carbon atoms and three nitrogen
atoms. The two isomers are: 1,2,3-triazole and 1,2,4-triazole. 1,2,4-Triazole and its derivatives
represent one of the most biologically active class of compounds and are associated with diverse
pharmacological activities [31-35]. The substituted 1,2,4-triazole nucleus is particularly common
and can be found in marketed drugs such as fluconazole, terconazole, rizatriptan, alperazolame
and triazolame [36]. A large variety of 1,2,4-triazole derivatives possess antibacterial antifungal,
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antiviral, anti-inflammatory, anticonvulsant, antidepressant, antitubercular, antitumoral,

antihypertensive, analgesic, enzyme inhibitor, hypoglycemic, sedative, hypnotic, antiparasitic,
herbicidal, insecticidal and plant growth activities [37-42]. Thus several potent drugs possessing
triazole nucleus have been applied in medicine like, alprazolam (anxiolytic, tranquilizer),
anastrozole, letrozole, vorozole (antineoplastics, non-steroidal competitive aromatase inhibitors),
estazolam (hypnotic, sedative, tranquilizer), etoperidone (antidepressant), fluconazole,
itraconazole, terconazole (antifungl agents), ribavirine (antiviral agent), benatradin (diuretic),
rilmazafon (hypnotic, anxiolytic, used in the case of neurotic insomnia), nefazodone
(antidepressant, 5-HT2 A-antagonist), rizatriptan (antimigrain agent), trapidil (hypotensive),
prazodone (antidepressant, anxiolytic, selectively inhibits central serotonine uptake) and
triazolam (sedative and hypnotic). The triazole antifungal drugs include fluconazole,
isavuconazole, itraconazole, voriconazole, pramiconazole, and posaconazole. The triazole plant
protection fungicides include epoxiconazole, triadimenol, propiconazole, metconazole,
cyproconazole, tebuconazole, flusilazole and paclobutrazol [43-48].
Biological activity of 1,2,4-triazole derivatives: Various work are available with regard to the
study of 1,2,4-triazoles. The literature revealed that the compound containing 1,2,4-triazole are
reported to possess diverse biological activities. Some 1,2,4-triazole fused acyclic and membered
macro cyclic compounds (1) with potential antimicrobial activity[49]. The 1,2,4-triazoles
derivative (2) with antibacterial activity against Staphylococcus aureus, Klebsiella pneumonia,
Escherichia coli and Pseudomonas aeurogenosa using cup-plate method [50]. Some 1,2,4-
triazole analogues (3) for evaluation of their antifungal activity against C. albicans, A. niger
[51]. Some new 1,2,4-triazoles and their Mannich and Schiff bases (4) and screened for their
antimicrobial activity against E. coli, Y. pseudotuberculosis, P. aeriginosa, Enterococcus
faecalis, S. aureus, B. cereus, C. tropicalis and C. albicans [52]. Some 1,2,4-triazole derivatives
(5) and have shown the activity against E. Coli, klebsiella pneumonia, Yersinia
pseudotuberculosis, Enterobacter aerogenes, P. aeurogenosa, staphylococcus aureus, E.
faecalis, Bacillus cereus, Candida tropicalis, C. glabrata [53]. Some new 1,2,4-triazole
derivatives (6) and screened for their biological activity in vitro against Gibberella zeae,
Alternatia solani [54]. Some 1-acylthiosemicarbazides, 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and
1,2,4-triazole-3-thiones (7) has described activity as anti-inflammatory by carrageenan Paw
Edema Test (CPE) method [55]. Some 1,2,4-triazoles (8) starting from isonicotinic acid
hydrazide and evaluation of their antimicrobial activities against E. coli, Y. pseudotuberculosis,
P. aeruginosa, Enterococcus aureus, Bacillus cereus, C. tropicalis and C. albicans, by Agar-well
diffusion meyhod [56]. The 5-aryl-3-alkylthio-1,2,4-triazoles (9) and sulfones with anti-
inflammatory activity and also analgesic activity [57]. The 1-acylthiosemicarbazides, 1,2,4-
triazole-5(4H)-thiones (10), 1,3,4-thiadiazoles and hydrazones containing 5-methyl-2-
benzoxazolinones showed analgesic activity, anti-inflammatory activity and also antimicrobial

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activity against Candida krusei, Candida albicans and Candida parapsilosis. The 4H-1,2,4-
triazole derivatives (11) which have shown analgesic activity [58].
H
N N

S
N

N N H
N N N N
N
O NH R
CH2 CH3 S
S N
N H O
H O N
Compounds (1) Compounds (2) Compounds (3)
N N

SH
O N N
N N

O N
N O
N N Cl
N CH3
NH
S
N N
N R
O N
O O
CH3

Compounds (4) Compounds (5) Compounds (6)

N N N
N H
N CH3
S N N

N S
N N

N N
H
O N N
CH2
- S O O R
F Ar N
Compounds (7) Compounds (8) Compounds (9)
H
N N
N N
S
CH2 N SH
N R N R'
H3C H3C
C O N N N
O
R"
Compounds (10) Compounds (11)

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O N
N
Cl N N
H N
CH 3
N CH3
N S
N N
N N
N N N

S O O O
Compound (12) Antibacterial [59] (13) Antimicrobial [60] (14) Antibacterial [61]
CH 3 Br
F
O O
CH 3
O O
S
H
N S N
N N N
Br
HS
N N N
N N N
N
N
(15)Antifungal [62] (16) Anticonvulsant [63] (17) Antibacterial [64]
N NH
O
Cl
N S
Cl O
N CH 3
N NH (19) Anti-inflammatory [66].
Br
S
(18) Anti-inflammatory[65].
Figure 1. Structure of some 1,2,4-triazole derivatives.

Recent Advancements
Recent literature survey demonstrates that the 1,2,4-triazoles are becoming of great practical
significance. 1,2,4-triazole derivatives possess analgesic, antipyretic and antiphlogistic
properties. A group of 1,2,4-triazole-5-ones and their mannich bases have shown antitubercular
activity [67] and have been investigated with regard to their mode of action.
Anticancer activity: A series of compound 3-(2,4-dichloro-5-fluorophenyl)-6-(substituted
phenyl)-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines (19) compounds were tested for their antitumor
activity. Among the compounds, compound 19a, 19b and 19c exhibited most potent activity
against sixty cancer cell lines of leukemia, non-small cell lung cancer, melanoma, ovarian
cancer, prostate and breast cancer [68].
A series of novel alkyltriazole tagged pyrido[2,3-d]pyrimidine derivatives (20). These
derivatives were then screened for their in-vitro anticancer activity against three cancer cell lines
such as U937, THP-1 and Colo205. Compounds 20a and 20b showed potent anti-cancer activity
against the respective cell lines [69].

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N
N
S CF3 O R1
F N
N
N N
N
Cl N
Cl N N R
R

R= 19a; 4-Cl, 19b; 2,4-Cl 19c ; 2,4Cl -5-F 20a: R= H, R1= CH3-(CH2)8-CH2;
20b: R= CH3, R1= CH3-(CH2)8-CH2
Anticonvulsant activity
A series of 6-alkoxy-[1,2,4] triazolo [4,3-b] pyridazine derivatives (21) and screened them for
anticonvulsant activity. In all synthesized derivative, 6-(2, 4-dichlorophenoxy)-[1,2,4] triazolo
[4, 3-b] pyridazine 8 was found to be most active and exhibiting the lowest toxicity [70] A series
of 4,5-diphenyl-2H-1,2,4-triazol-3(4H)-one (22) compounds and screened them for their
anticonvulsant activity. Compounds 22a, 22b, 22c-g were exhibited potent anticonvulsant
activity in all the four animal models of seizure which are maximal electroshock seizure (MES),
subcutaneous pentylenetetrazole, subcutaneous strychnine, and subcutaneous picrotoxin -induced
seizure threshold tests [71].

N
HN
R
N
Cl O
N O
N R2
N
N Cl R1
21 22
R, R1, R2 22a: H, 2-CH3, 4-CH3; 22b: H, 2-CH3, 5-CH3; 22c: NO2, H, 4-F; 22d: NH2, H, 4-F;
22e:CH3, H, 4-F; 22f: H, H, 4-F; 22g: OH, H, 4-F

Antimicrobial activity: A series 5-(4-amino substituted-8-(trifluoromethyl) quinolin-3-yl)-4-

(un) substituted phenyl -4H-1,2,4-triazole-3-thiols (23) from derivatives of 4-hydroxy-8-
(trifluoromethyl) quinoline-3-carbohydrazide and screened for their antimicrobial activity against
E. coli, S. aureus, P. aeruginosa, K. neumonia. The activity of these compounds was compared
with ciprofloxacin as standard drug. The compounds 23a, 23b and 23c showed comparatively
very good activity against all the bacterial strains [72]. A series of novel sulfanilamide-derived
1,2,3-triazole compounds (24 and 25) via 1, 3-dipolar cycloaddition and screened them in vitro
for their antibacterial and antifungal activities against S. aureus, E. typhosa, P. aeruginosa, S.

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dysenteriae, B. subtilis, E. coli, as well as C. albicans and C. mycoderma. The activity of the
synthesized compounds was compared with the reference drug chloramphenicol. The compounds
24, 25a and 25b bearing dodecyl, 2,4-dichlorobenzyl and 2,4-difurobenzyl group, respectively,
showed the most potent antibacterial activities against all tested bacterial strains with the MIC
values ranging from 32 to 128 μg/mL[73].

SH O H
R1 H N
O N S
R2 N
S O
N N N
O
N N N (CH ) CH N
2 11 3
N
R3
N
NH 2
CF3 R2
NH 2 R1
Figure 24 Figure 25
25a R1 = Cl, R2 =H, R3 = Cl;
R1= Ph, -CH2Ph, -CH2CH2OMe; R2=
25b R1 = F, R2 = H, R3 = F
substituted amines; 23a: cyclopropyl
amine, 23b: cyclohexyl amine, 23c: 3,3
Dimethyl butylamine. 23d: Piperidine-4-
propanol, 23e:Morpholine, 23f: 4-
Piperidine morpholine

Anti-inflammatory activity: A series of several new 6-alkoxy (phenoxy)-[1,2,4]triazole [3,4-a]

phthalazine-3-amine derivatives (26). All synthesized derivative further screened for their anti-
inflammatory activity. The compounds 26a and 26b possess highest anti-inflammatory activity
in comparison to the reference drug Ibuprofen [74].
Anti-oxidant activity: A series of 4-(3,4-dihydroxyphenethyl)-5-methyl-2H-1,2,4-triazol 3(4H)-
one derivatives (27 and 28) which were then screened for anti-oxidant activity. It was found that
compounds 27a-d and compound 28 possess highest degree of antioxidant activity [75].

R H H
O N O N O
N N
N N OH N OH
N (Ar)R HO
NH2 OH OH
N N HO

26a: R = -C6H4 (o-Cl); 27a-d 28

26b: R = -C6H4 (p-NH2)

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4-(2,3-dihydroxyphenethyl)-5-(3,4-dihydroxybenzyl)-2H-1,2,4-triazol-3(4H)-one

Compound: 26a 26b 26c 26d

Ar: -CH3 -CH2CH2CH3 -C6H5 S

A series of 3-alkyl (aryl)-4-(3,4-dihydroxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-one

(29) and were evaluated for their antioxidant activity by DPPH free radical scavenging method.
Among the compounds 29a, 29b shows more potent antioxidant activity.
Anti-malarial activity: A series of chalcone and dienone hybrid compounds (30) containing
aminoquinoline and nucleoside templates which were then screened for in-vitro antimalarial
activity. Amongst the compounds, three compounds were found to be most active that is
compounds 30a, 30b and 30c, compound 30a was the most active and potent against D10, Dd2
and W2 strains of P. falciparum compared with the standard drug chloroquine [76].
Anti-tubercular activity: Various derivatives of substituted 1,2,4-triazol-(3-yl) benzene-1,2,3-
triol derivative (31) and screened them for anti-TB activity. It was found that compounds 31a
and 31b possess comparable activity with that of standard drug Rifampicin against M.
tuberculosis. The remaining compounds are found to be less active than standard [77].

HO
Cl N
R N
R HO H
N
OH N
N
N N H3CO N HO
HN N
OH N N R
O
O

29a:R=CH3; 29b:R=CH2C6H5 R 30a: 2,4-diOMe; 30b: 2,3,4-triOMe; 31a: NO2; 31b: OH

30c: 2, 3, 4-triOMe

Anti-nociceptive activity: A series of 1-[2-(1H-tetrazol-5-yl) ethyl]-1H-benzo-1,2,3 triazole

derivative (32) were screened for anti-nociceptive and anti-inflammatory activity. It was found
that compounds 32a and 32b possess significant anti-nociceptive activity while compounds 32c
and 32d possess significant anti-inflammatory activity [78,79].

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R
N O O
N O O O O
N N S S
N
N
N
32a R= NH 2 , 32b OH , 32c H 3C ,32d H 2N
From the above discussions it may be concluded that the modifications in triazole moiety
displayed valuable biological activities and these modifications can be utilized to develop
potentially active agents for future investigations.
In the last few years, heterocyclic compounds have attracted strong interest and a lot of work has
been done on triazole ring. Many different derivatives have been prepared from it which
possesses useful pharmacological activities. In the present review, we have compiled the
different pharmacological activities of triazole ring and its derivatives. It has been observed that
triazole derivatives possess a wide range of pharmacological activities. In triazole ring,
substitution at 1,4 and 1,3 positions of a more electronegative group will possess more active
analogues. This review contains various pharmacological activities of triazole in one place and it
is also the milestone for the new research towards this moiety. Medicinal chemistry is an aspect
of biological, medical and pharmaceutical sciences. It is concerned with the invention, discovery,
design and identification of biologically active compounds. It also involves study of metabolism,
interpretation of mode of action at the molecular level and the development of structure activity
relationship (SAR) of the active nuclei. It is devoted to the discovery and development of new
agents for treating diseases. Inorganic compound continue to be important in therapy, for
example, antacids, mineral supplements and radiopharmaceuticals, but organic molecules with
increasingly specific pharmacological activities are clearly dominant. Heterocyclic compounds
are cyclic compounds with at least two different elements as ring member atoms. They are the
counterparts of homocyclic compounds, which have only ring atoms from the same element.
Although heterocyclic compounds may be inorganic, most contain at least one carbon atom, and
one or more atoms of elements other than carbon within the ring structure, such as sulfur, oxygen
or nitrogen. In organic chemistry noncarbons which replace carbon atoms are called heteroatoms
[80-84]. Triazole and its derivatives possess a great significance in medicinal chemistry and
numerous heterocyclic compounds containing triazole with different biological activities can be
synthesized from them. Triazole has a basic, five membered, heterocyclic ring containing two
carbon and three nitrogen atoms. It forms a pair of isomeric chemical compounds [85]. Out of
these two, 1, 2,4-triazole possess significant and wide variety of activity in comparison to 1,2,3-
triazole. 1,2,3-triazole is considered to be the most stable organic compound in comparison to all
other organic compounds possessing three adjacent nitrogen atoms. Aziridine was formed by
flash vacuum pyrolysis from 1,2,3-triazole at 500°C which leads to loss of molecular nitrogen
(N2). Certain triazoles undergo cleavage very easily due to socalled ring-chain tautomerism such
as in the Dimroth rearrangement. 1,2,3-triazole is considered to be the most useful component,
widely used in research purpose as a building block for complex chemical compounds such as

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pharmaceutical drugs like tazobactam. 1,2,4-Triazole is a basic aromatic heterocycle and its
derivatives posses a wide variety of pharmacological activities. Some of the marketed
preparation which contains triazole ring is fluconazole and itraconazole. The attachment of
quinoline ring to triazole ring is responsible for producing anti-bacterial effect and further
modifications can be made on it to enhance its pharmacological effect. Substitution at 3rd
position may also increase the pharmacological activity of a compound for e.g.:- 3-Amino-1,2,4
triazole is a competitive inhibitor of the production of HIS3 gene, imidazoleglycerolphosphate
dehydratase. It is an enzyme catalyzing the sixth step of the histidine production and is also a non
selective systemic triazole herbicide used on non food crop land to control annual grasses and
broad leaf and aquatic weeds [88].

OH N O O H 3C CH3
N O N
N O H 3C CH3 O
N N
N N O
N
N O Cl N
F N Cl N
N N
F
N
Itraconazole (Antifungal)
Posaconazole (Antifungal)
H 3C O
N CH3
N O
O N
N N N
N
Cl O N NH 2 H 3C
N
O

Cl
Cl Nefazodone (Antidepressant)
Rilmazafone (Anxiolytic)
N O N
HO H 3C N CH3
N
NH2
N N N N
HO N
F OH OH O
H 3C N N
Ribavirin (Antiviral)
Trapidil (Anti-hypertensive
N
F N Vasodilator)
N
Fluconazole (Antifungal)

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Cl H3 C CN N
CH 3 N
F N
H 3C H 3C CH3 F
N NC
N H 3C N
N F OH
N N N N
N
Alprazolam (Tranquillizer)
Anastrozole (Antineoplastic) Voriconazole (Antifungal)
Cl N Cl
F N
N
O
NH 2 N N N
F N
N
N O
N
N N
Rufinamide (Antiepileptic)
Estazolam (Sedative-Hypnotic) Trazodone (Antidepressant)

Figure 2. Some triazole based drugs available in clinical Uses [89-100].

Synthesis of 1, 2, 4-triazole backbone: There are various methods for synthesis of 1,2,4-
triazole are available in literature which involve conventional one pot, multi -components,
microwave assisted, under free condition, regioselective. Einhorn-Brunner [101-104]
reported synthesis of a mixture of isomeric 1,2,4-triazoles from the reaction of imides with
alkyl hydrazines in presence of acyl hydroxide (Scheme 1). The synthesis of substituted
1,2,4-triazole by the reaction of an amide and a hydrazide [105] (Scheme 2).

H R3
O O R3
AcOH N N
N
R1 N R2 R3 NH 2 R2 R2
R1 N
H R1

Scheme 1: Synthesis of a mixture of isomeric 1,2,4-triazoles using imides with alkylhydrazines

in presence of acyl hydroxide.

H
O O
R' N
NH 2 R
R' N R NH2
N N
H

Scheme 2: Synthesis of a substituted 1, 2, 4-triazole from amide and a hydrazide

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A highly regioselective one-pot process provides rapid access to highly diverse 1,3,5-
trisubstituted 1,2,4-triazoles from reaction of carboxylic acids, primary amidines, and
monosubstituted hydrazines [106].
R'

O NH O R1
H2NNH-R'' N
N
R OH2 R1 NH2 R N NH 2 N
R
R'' R, R’R’’=alkyl, aryl

Scheme 3

An effective 1,3-dipolar cycloaddition for the synthesis of 1,3,5-trisubstituted 1,2,4-triazole

derivatives by reaction of oximes with hydrazonoyl hydrochlorides using triethylamine as a base
gave the desired 1,3,5-trisubstituted 1,2,4-triazoles in good yields. The reaction was applicable to
aliphatic, cyclic aliphatic, aromatic and heterocyclic oxime substrates [107].

ArHN Ar
NO.HCl N
N.HCl NEt3 N
COOCH 3
R H Cl COOCH 3 R' N

R= alkyl, aryl

Scheme 4

The 3-N, N-Dialkylamino-1, 2, 4-triazoles can be prepared from S-methylisothioureas and acyl
hydrazides in good yields. The reaction conditions are relatively mild and tolerate a broad range
of functional groups [108].
O N
SCH3 N
R''
R N
N N H2 N R'' N
R
NH 2 R'''
R' R''' R' R,R’, R”’ = alkyl, R’’= alkyl, aryl

Scheme 5

The [1,2,4] Triazolo[1,5-a]pyridines have been prepared in good yields from 2-aminopyridines
by cyclization of N-(pyrid-2-yl) formamidoximes under mild reaction conditions with
trifluoroacetic anhydride [109].

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OH
H
N N N
TFAA
THF N
N
R
R

Scheme 6

The bis-1,2,4-Triazole derivatives by the reaction of 3-Aryl-5-phenyl-4-amino-4H-1,2,4-triazoles

and bis-aldehydes to yield 1,2/1,3-bis[o-(N-methylidenamino-3-aryl-5-phenyl-4H-1,2,4-triazole-
4-yl)phenoxy]ethane/propane, derivatives. Compounds were reduced with NaBH4 to afford the
corresponding 1, 2/1, 3-bis [o-(N-methylamino-3-aryl-5-phenyl-4H-1,2,4-triazole-4-yl) phenoxy]
ethane/propane derivatives [110].

Scheme 7
Compound triazole derivatives as synthesized as below [111];
N
N
Br2 / gl. CH3COOH N N Formamide
NH2
NH 2
R-CH=NNH-CO-NH2 O Ethylene glycol R
N
R H

Scheme 8
The 1-monosubstituted aryl 1,2,3-triazoles was prepared in good yields using calcium carbide as
a source of acetylene. The copper-catalyzed 1, 3-dipolar cycloaddition reactions were carried out
without nitrogen protection and in a MeCN-H2O mixture [112].

N
CuI / Na ascorbate N
ArN3 CaC2 N Ar
CH3CN / H2O (2:1)

Scheme 9
Pd-catalyzed synthesis of 1H-triazoles from alkenyl halides and sodium azide represents a
completely new reactivity pattern in the context of Pd chemistry [113].

Br N
N
NaN3 NH
Ar Ar

Scheme 10
Cycloadditions of copper (I) acetylides to azides and nitrile oxides provide ready access to 1,4-
disubstituted 1,2,3-triazoles and 3,4-disubstituted isoxazoles, respectively [114].

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R N
CuSO4.%H2O N
R-N3 R N
Sod. Ascorbate
R' R= alkyl R’=PhCOOH
Scheme 11

Synthesized 1,2,3-Triazoles were prepared in good to modest yields by cycloaddition of alkyl

azides onto enol ethers under solvent-less conditions. The reaction can access ring-fused
triazoles that are unavailable by azide-alkyne cycloadditions and is easily scalable. The 1,2,3-
triazole products bear functionality that may be readily derivatized [115].
N N
N N
R' R' R'
R-N3 N N
H3 CO R R
OCH3

Scheme 12

Pellizari Reaction: The synthesis of 1,2,4-triazole derivatives by the mixture of amide and acyl
hydrazide is generally referred to as the Pellizzari reaction. It has been reported that heating the
mixture of formamide and hydrazine hydrochloride with KOH yield of 1,2,4-triazole. For
example benzamide and benzoyl hydrazide gave 3,5-diphenyl-1,2,4-triazole [116].
O HN N
O
NH2
NH 3 N
N 140 oC
H

Scheme 13

Einhorn-Brunner Reaction: The synthesis of 1,2,4-triazoles by condensation between

hydrazines or mono substituted hydrazine and diacylamines in the presence of weak acid is
known as the Einhorn–Brunner reaction. For example N formyl benzamide and phenyl hydrazine
gave 1,5-diphenyl-1,2,4-triazole [117].
NH 2
O HN H
N
CHO
N
H C2H5OH O N N
HN N
N

Scheme 14

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1,5-Diarylsubstituted 1,2,3-triazoles are formed by aryl azides and alkynes in DMSO in the
presence of a catalytic amount of tetra alkyl ammonium hydroxide. The reaction is simple, does
not require a metal catalyst [118].
Ar

N(CH3)4OH
Ar-N3 Ar' CH N Ar'
DMSO N
N
Scheme 15

Thiosemicarbazide on cyclization in alkaline medium afford 1,2,4-triazoles [119,120].

O S R N N
NaOH N NH
NH
HN NH N N
SH S
R R
R = Phenyl, 4-Methoxy phenyl, 3-methyl phenyl, 2-Flouro phenyl
Scheme-16

Thiosemicarbazides on heating with triethylamine in ethanol cyclizes to give 1,2,4-triazoles

[121].
O R
H N(C2H 5)3 N
N N H N S
N H N
R N NH
O S O
O
O
Scheme-17 R =substituted Aryl

Thiosemicarbazide on refluxing with 1,1 cyclopropane dicarboxylic acid and SOCl2 in alkaline
medium cyclizes to give 1,1-bis(3-thio-1,2,4-triazol-5-yl) cyclopropane [122].

O O N N
i. SOCl2, NH2NNCSNH2 N N
HO OH HS SH
ii. NaOH N N
H H
Scheme-18

2-Chloro-6-methoxy-4-phenyl-quinoline on refluxing with substituted acylhydrazides in a

nitrogen atmosphere yield 7-Methoxy-1-(4-methoxyphenyl)-5-phenyl-1,2,4-triazolo[4,3-a]
quinoline [123].

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N
N
Ph
Ph N
H 3CO i. RCONHNH2
ii. n-butanol

N Cl OCH 3
H3 CO
Scheme-19

(2E)-4-phenylquinolin-2(1H)-one hydrazone when refluxing with formicacid in ethanol yield 5-

phenyl-3,3a-dihydro [1, 2, 4]triazolo[4,3-a]quinoline [124].
H
H 2N N N
i. HCOOH N
ii. C2H 5OH N
HN

Scheme-20

1,2,4-Triazole-3,5-diamine derivatives were synthesized in moderate to high yields in one-pot

reaction from the corresponding isothiocyanates, monosubstituted hydrazines, and sodium
hydrogen cyanamide in the presence of 1-(3-dimethylaminopropyl)-3 ethylcarbodiimide
hydrochloride. Typically, two target compounds were obtained, but high regioselectivity to one
isomer was observed when aromatic and sterically bulky hydrazines were used. Examples with a
detailedrepresentative procedure are given below [125,126].

R2 R2 N
i.NaNHCN N NH 2
N N
ii.R2NHNH2 N
R1NCS R1 NH 3 R1 N
EDC N N
H H
R1/R2 = Alkyl, Aryl
Scheme-21

The N-(4-methylsulfonylphenyl)aryl carbohydrazonamides undergoes a ring closure using 1,1 -

thiocarbonyldiimidazole and subsequent alkylation to afford 5-(4-halophenyl)-4-(4-
(methylsulfonyl)phenyl)-2H-1,2,4-triazole-3(4H)-thione [127].

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O O
H3C
S H3 C
O S O

X 1,1'-thiocarbonylimidazole X

HN
N
S
N
NH 2 HN N

Scheme-22

The reaction of N, N-dimethylformamide azine with primary amines mediated by p-toluene

sulfonic acid gives the triazole as shown in scheme-9. The driving force of this reaction is the
release of dimethyl amine as well as the stability of the triazole formed [25].

H 3C
CH 3 N
N p TosOH
N NH3-R N R
H 3C -2 HN(CH3)2 N
CH 3 R = Alkyl/Aryl
Scheme-23

1,3,4-oxadiazole on reaction with the primary amines gives 3,5-disubstituted 1,2,4-triazole [128].
R1

H 3C O
R1 p TosOH N
NH 2 N
N N -H2O N
R2
R2
CH3
Scheme-24 R1/R2 = Alkyl/Aryl

(Z)-4-chloro-N'-(ethoxy(p-tolyl)methylene)benzohydrazide undergoes cyclization in presence of

hydrazine monohydrate to produce 4-amino-3-(pchlorophenyl)-5-p-tolyl-4H-1,2,4-triazole
[129,130].
Cl H 2N
CH 3 i. Propanol Cl
O ii. R2NHNH2 N
H 3C
H3 C
N
N N N
H O
Scheme-25

Reaction of resin bound S-methyl isothiourea with carboxylic acids yielded resin-bound S-
methyl-N- acylisothiourea which reacted with hydrazines under mild conditions to afford the
corresponding resin-bound 3-amino-1,2,4-triazoles with regioselectivity [131].
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Asif & al. / Mor. J. Chem. 2 N°3 (2014) 136-164

H3C R2
i. DMF N
O S O N
ii. R2NHNH2
R1
O N N R1 iii.TFA/DCM H 2N N
H H
Scheme-26

When substituted phenylthiourea is refluxed with 2-(aryloxy)alkanoic hydrazides in presence of

pyridine, it gave 1,2,4-triazole. The completion of the reaction was assured by the ceasing of the
methylmercaptane evolution [132].
O N
O NH
H
N NH 3 O Pyridine
NH S
O NH2 R
R

Scheme-27 R=CH3, Cl, Br,

Triazole synthesis using microwave: Microwave synthesis reduces the reaction time resulting
in more decision point per unit time rather then days. The short reaction time provided by
microwave synthesis makes it ideal for rapid reaction scouting and optimization of reaction
conditions, allowing very rapid. In order to fully benefit from microwave synthesis one has to be
prepared to fail in before succeeding. While failure could cost a few minutes, success would gain
many hours or even days. The 4,5-Disubstituted-1,2,4-triazole-3-thiones have been prepared in
one stage from the reaction of acid hydrazide with alkyl or aryl isothiocyanate in the presence of
a KOH (10%) solution on the surface of silica gel as well as on the surface of montmorillonite
K10 under microwave irradiation. These triazoles have also been prepared from the reaction of
4-substituted-1-aroyl thiosemicarbazides, with a KOH (10%) solution on the surface of silica gel
under microwave irradiation [133].
O O
H H
NH2 R2NCS N N
R1 N R1 N R2
H H
mo
ntm H S
or i N KO
llo R CH 3 10%
n O3
MW ite K101 N
W , Si
M
N
R2 S
Scheme 28 R1 -CH3, C6H5, 4-Cl-C6H5, 4-NO2-C6H5; R2 –CH3, C6H5

Different types of 4,5-disubstituted 1,2,4-triazole-3- thiones by microwave irradiation as well as

by a classical method. The beneficial effect of microwave irradiation on the dehydrative
cyclization of thiosemicarbazides in different reaction media is described. The results show that

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the effect of microwave irradiation on the reaction studied was the shortening of reaction times
(from 2–9 h to 2–4 min) and a minor decrease (1–4%) of yields [134].
S
H MW
R N R1 R SH
N N
H H R1
O
Scheme 29 R- Benzyl, 2- methyl phenyl; R1–2-pyridyl ,3-pyridyl, 4-pyridyl

Synthesized 3,5-disubstituted-4-amino-1,2,4-triazoles from the reaction of aromatic nitriles with

NH2NH2·2HCl in the presence of NH2NH2·2H2O excess in ethylene glycol under microwave
irradiation [135].
NH2
Ethylene glycol Ar N
Ar-CN Ar
NH2NH2.2H2O
N N
NH2NH2.H2O
Scheme 30

A novel one-step synthesis of thiazolo-[3,2-b]-1,2,4-triazoles were reported from the reaction of

chalcones with bis-(1,2,4-triazolyl)-sulfoxide [136].
O R1
O
R1 R2 S N N
N N Toluene
N N
N N N S R1
O
Scheme 31

Symmetrical 3,5-substituted-4-amino-1,2,4- triazoles are quickly prepared from aromatic

aldehydes via nitriles by two-step reactions without any separation under microwave irradiation
for several minutes [137].
Ar
NH2
NH2NH 2.HCl
NH2OH.HCl NH2NH2. H2O N NH Ar N
Ar
ArCHO ArCN HO(CH2)OH
CH 3 N NH
N MW

O Ar
Scheme 32

4.6.Condensation of acid hydrazide with S-methylisothioamide hydroiodide and ammonium

acetate on the surface of silica gel under microwave irradiation afforded 1,2,4-triazoles [138].
O H 3C NH4OAc H
S N R2
R1
NH3 I- Et 3N, MW
R1 N R2 NH 2
H N N

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Scheme 33

An efficient microwave-assisted one-pot and three-component synthesis of substituted 1,2,4-

triazoles has been achieved utilizing substituted primary amines [139]. A efficient one-step,
basecatalyzed synthesis of 3,5-disubstituted 1,2,4-triazoles by the condensation of nitriles and
hydrazides under microwave irradiation [140].
R2 H
O N
K2 CO3 , n-BuOH
R1CN NH2 N
MW N
R2 N
H
R1
Scheme 34

Under the reaction conditions, a diverse range of functionality and heterocycles are tolerated.
The reactivity of the nitrile partner is relatively insensitive to electronic effects. A new protocol
for Biginelli reaction microwave irradiation in the synthesis of some 1,2,4-triazoles as a potential
antifungal agents against C. albicans and A. niger has been reported recently [141].
N NH
HN
N S

R1
R2
Synthesized new antifungal azoles including 1,2,4-triazole derivatives from substituted
hydrazide using various solid supports under microwave irradiation [142].
R
O
H N N
N
N R S
H N
H
NH NH4SCN
Basic/neutral alumina MW NH
O
O

Scheme 35

A simple and fast synthesis of 6-aryl-3-substituted 5H-[1,2,4]-triazolo-[4,3-b][1,2,4]- triazoles in

high yields has been developed by microwave aided heterocyclization of N-(3- methylthio-5-
substituted 4H-1,2,4-triazol-4-yl)-benzenecarboximidates [143].

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R
R
H
N N
HN N N
N N
N N
NH S
CH 3
Scheme 36

Discussion
In the previous years the synthesis of high nitrogen containing heterocyclic systems has been
attracted to many pharmaceutical and agrochemical industries. Triazole is a five member
heterocyclic nucleus has attracted a wide attention of the Chemist in search for the new
therapeutic molecules. The triazole nucleus is one of the most important heterocycles which is a
feature of natural products and medicinal agents. Triazole nucleus is enjoying their importance as
being the center of activity. The nitrogen containing heterocyclics are found in abundance in
most of the medicinal compounds. The triazoles are said to be the isosters of imidazoles in which
the carbon atom of imidazole is isosterically replaced by nitrogen. Triazole and its derivatives
have a wide range of application and play vital role in biological fields [144-146]. These
Skeletons have its multiple potential against several activities. In the last few decades, the
chemistry of triazoles and their fused heterocyclic derivatives has received considerable attention
owing to their synthetic and effective biological activities. Also, there are known drugs in market
containing the triazole group e.g. fluconazole, intraconazole, voriconazole, Triazolam,
Alprazolam, Etizolam and Furacylin. This review includes the Microwave synthesis of triazoles
and its reported derivatives. The derivatization of Triazole ring is based on the phenomenon of
bioisosterism in which replacement of oxygen of oxadiazole nucleus with nitrogen triazole
analogue. This review provides a brief summary of the medicinal chemistry of triazole system
and highlights some examples of recent drug containing this moiety in the current literature.
Triazole is a unique moiety that is responsible for various biological activities. This article
highlighted research work of many researchers reported in literature for different
pharmacological activities on synthesized triazole compounds.
This review has presented comprehensive details of triazole analogues, potent compounds
reported for particular pharmacological activity and the method or technique involved in
evaluation process [147,148]. More investigations must be carried out to evaluate more activities
of triazole for many diseases whose treatment are difficult in the medical sciences.
This has been noticed so far, that modifications on triazole moiety results in the formation of
compounds with valuable biological activities. It will be interesting to observe that these
modifications can be utilized as potent therapeutic agents in future. Thus many more

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modifications on triazole moiety can be possible and needs to be continued for the use of
mankind.
Conclusion
1,2,4-Triazoles have attracted considerable attention in the fields of medicine and agrochemical
research as well as in materials science, due to their unique structures and properties. 1,2,4-
triazole and its derivatives belong to a class of exceptionally active compounds possessing many
pharmacological properties.Some of the derivatives of triazoles are also known to exhibit
anticancer activity. 1,2,4-Triazoles have clinched much importance as they have also been
investigated for their CNS depressant, pesticidal, anti-mycobacterial, hypoglycemic, diuretic,
insecticidal and herbicidal effects. Sulfonamide drugs (sulfa drugs) were the first antimicrobial
drugs that paved the way for the antibiotic revolution in medicine. From a structural point of
view, sulfonamides are interesting because of their tendency to form different hydrogen bonded
systems in the solid state by introducing various hydrogen-bond donors and acceptors as
substituents into simple sulfonamide molecules. Moreover, sulphur containing heterocycles
represent an important group of sulphur compounds that are promising for use in practical
applications. Among these heterocycles, the mercapto- and thione-substituted 1,2,4-triazole ring
systems have been well studied and so far a variety of biological activities have been reported for
a large number of their derivatives. It is well established that various derivatives of triazole
exhibit broad spectrum of pharmacological properties. The 1,2,4-triazole moiety present in the
various natural products and the synthesis of compounds. This moiety has attracted attention of
chemists as well as biologists. The compounds containing different heterocyclic moiety would be
tested for antimicrobial activity against different strains of pathogenic organisms. Similarly few
of the compounds would also be screened for anti-inflammatory and analgesic activities. Many
of the available therapeutically important medicines such as ketoconazole, itraconazole,
voriconazole and fluconazole contain this heterocyclic nucleus. In view of the above mentioned
facts and in continuation of interest in the heterocycles containing 1,2,4-triazole moiety to
identify as new molecule that may be value in designing new, potent, selective and less toxic
antimicrobial agents. This combination is thought in an attempt to investigate the influence of
structure variation on the anticipated biological activities, hoping to add some synergistic
biological significance to the target molecules.

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