Introduction

Cancer is the 2nd more life threatening disease occurring after cardiovascular
diseases and remains to be the leading cause of death in humans around the world for
few decades [1,2]. According to the World Health Organization (WHO) survey, in
2015, approximately, 8.8 million people died globally [3]. It has also been reported
that in coming decades, the mortality rate will increase, as a result of different types of
cancer all over the world [4, 5]. Therefore, efforts have been made to treat and prevent
cancers with respect to the effect of disease anomaly on the long term well-being of
people [6]. In this regard, one of the major interest in drug discovery is the search for
new anticancer agents. Therefore, we’ve found 1,2,4-triazoles and its derivatives as an
emerging class having anti-cancer activity. 1,2,4-Triazoles are the important class of
5-membered ring heterocyclic compounds with a wide range of applications in the
field of material sciences, agro-chemicals and pharmaceuticals [7]. A number of 1,2,4-
triazole derivatives are reported to have bio-activities like anti-viral [8], anti-
hypertensive [9, 10], anti-fungal, anti-microbial [11], anti-inflammatory [12], anti-
bacterial [13], hypoglycemic [14], anti-depressant [15], anti-convulsant [16],
antiplatelet [17] anti-malarial [18], anti-migraine [19], anti-diabetic [20], arthritis [21],
anti-leishmanial [22], anti-tubercular [23], potassium channel activators [24], analgesic
[25], and antioxidant [26]. 1,2,4-triazole derivatives have also been commercialized as
essential plant growth regulators, herbicides [27] and fungicides [28]. The 1,2,4-
triazole nucleus shows a wide spectrum of anti-cancer activities, target specificity and
is metabolically stable. It can act as donor or acceptor of hydrogen bond at the active
site of the receptors due to the presence of three nitrogen atoms and consequently, can
also regulate their activity at reactive site. Due to the polar nature of 1,2,4-triazole
nucleus, the solubility of ligands can increase and as result have better
pharmacodynamic and pharmacokinetic properties [29]. In many cases, 1,2,4-triazole
nucleus behaves as a linker with which different moieties are attached as
pharmacophore and at the same time it initiates requisite flexibility to the drug for
potent ligand-receptor interactions. There have been written a lot of review articles on
the synthesis and bio activities of triazoles and their derivatives [30-33]. This review
article is based on the study of several reports on the anti-cancer, prospective of 1,2,4-
trizole derivatives.
1,2,4-triazole Based Anti-Cancer Compounds

The 1,2,4-triazole nucleus is present in a variety of structurally different anti-

cancer compounds. This nucleus is explored extensively in indole derivatives , Schiff
bases of triazoles , bridged triazoles compounds and metal complex based anti-cancer
agents and nucleosides. The review article is based on either chemical structure of
triazoles nucleus with ligands or target receptor sites.

Indole derivatives of 1,2,4 triazoles

A series of 5-(3̕-indolyl)-3-substituted-1,2,4-triazoles were synthesized by

Kumar et al in 2011 and screened against pancreatic (PaCa2) , prostate (DU145, PC3
and LnCaP) and breast (MDA-MB-231 and MCF7) cancer cell lines (Table 1). These
compounds have shown significant anticancer activity with IC50 values ranging from 1
μM to 1 mM concentration. Compounds 3-(5-(3-methoxyphenyl)-4H-1,2,4-triazol-3-
yl)-1H-indole 1a and 3-(5-benzyl-4H-1,2,4-triazol-3-yl)-1H-indole 1b with
methoxyphenyl and benzyl groups at C-3 position of 1,2,4-triazole exhibited selective
cytotoxicities against Prostate (PC3 and DU145) cancer cell lines with IC 50 = 58 and
57 μM, respectively. The introduction of 4-hydroxy group in C-3 phenyl ring of 1,2,4-
triazole led to the synthesis of 4-(5-(1H-indol-3-yl)-4H-1,2,4-triazol-3-yl)-2-
methoxyphenol 1c with enhanced anticancer activity. Likewise, a more bulkier 4-
benzyloxy-3 methoxyphenyl group was introduced and 3-(5-(4-(benzyloxy)-3-
methoxyphenyl)-4H-1,2,4-triazol-3-yl)-1H-indole was synthesized that was more
effective against breast cancer (MCF7) with IC50 =7.1 μM and prostate cancer
(DU145 and LnCaP) cell lines with IC 50 = 8.9 lM and 8.5 lM, respectively. These
results suggested that a large group in the C-3 phenyl ring is more tolerable for
anticancer activity. Therefore, 3-(5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-
1H-indole 1e was synthesized with potent cytotoxic activity against Pancreatic
(PaCa2) cancer cell line with IC50 values = 83.3 μM. Kumar et al also synthesized 3-
(5-(4-fluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-1H-indole 1f which exhibited
selective cytotoxicity against Prostate cancer (PC3) cell line (IC50 = 4.0 μM).

N N
N N
NH OCH3 NH

N 1a N 1b
H H

OH
O
N O
N
N O
NH
N
NH
N 1c
H 1d
N
H

O
O F

N O N
N N
NH N

N 1e 1f
N
H H

O
N
N
N

N 1g
H
 The compound (1g) due to the presence of 3,4-dimethoxyphenyl ring at C-3
showed improved activity against all cancer cell lines with best results against breast
cancer (MCF7) and Prostate (DU145) cancer cell lines with IC50 = 8.1 and 5.8 μM,
respectively [37].

Schiff Base Derivatives of 1,2,4-Triazoles

The 1,2,4-triazoles Schiff base compounds like 1-(4-phenyl-5-thioxo-[1,2,4]triazol-3-

yl)methyl-5-oxo-[1,2,4]triazoles and 1-(5phenylamino-[1,3,4]thiadiazol-2-yl)methyl-
5-oxo-[1,2,4]triazole and their derivatives (2a) for antimicrobial and anticancer
activities were evaluated against three human tumor cell lines, NCIH460, MCF7, and
SF-268. The growth of MCF7 cell lines was decreased by these compounds. The
compound (2b) was found potent against breast tumor lines with a GI 50 = 1.87 μM
effective. The anti-proliferative activity of 1,2,4-triazole-based Schiff bases was also
studied. The synthesis of D-glucopyranosyl-1,2,4-triazole-3thione derivatives (2c)
was reported by Li et al. in 2009 [38] and these compounds were evaluated against
human Bel-7402 and MCF-7 cancerous cell lines for cytotoxicity. From the structure
activity relationship and cytotoxic activity it was found that introduction of 2,3,4,6-
tetra-O-acetyls-Dglucopyranosyl functionality into the 1,2,4-triazole-3-thione nucleus
has enhanced the activity of this series of Schiff base compounds. Besides this [39] the
quinolone-based Schiff’s bases are also a source of strong anti-tumor agents. A
number of substituents were incorporated at position 8 of quinolone and these were
evaluated in vitro against human breast cancer lines MDAMB231 and human colon
cancer cell lines (HT29). Besides these, various compounds have been reported such as
1,2,4-triazole derivatives (2d) exhibiting moderate to high anti cancer activity against
MDAMB231 = IC50 values between 48.2µM and 4.6 µM. Among these, the most active
compound in the series was a Schiff’s base with IC 50 = 4.6µM and 4.7 µM against
MDA-MB231 and HT29 cell lines, respectively.
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