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Letters in Organic Chemistry, 2013, 10, 693-714
693
Abstract: 1,2,4-Triazoles and their derivatives have a distinct place in the field of medicinal and pharmaceutical chemistry. These are used as lead compounds for the synthesis of numerous heterocyclic compounds which possess diverse
biological activities and play pivotal roles. This review covers the latest literature and knowledge on the synthetic
procedures for various triazoles derivatives, their activities and pharmacological applications.
1875-6255/13 $58.00+.00
Triazoles form an important cluster among the heterocyclic compounds which possess a wide range of biological applications. While Pellizari et al. [9, 10] have reported the
ability of 4-phenyl-1,2,4-triazoles to produce convulsions,
indeed 1-phenyl-1,2,4-triazole was found to exhibit anticonvulsant property [11]. Benzimidazolyl-1,2,4-triazole acts as
central nervous system depressant [12]. Besides these, the
nitrofuryltriazoles (1) display potential urinary track antibacterial activity [13]. The -amino--phenyl-o-tolyl-1,2,4triazoles (2) were reported as sedative and anticonvulsant
agents [14].
Apart from these, the 1,2,4-triazole derivatives possess
important pharmacological activities such as antifungal and
antiviral [15] properties. Examples of antifungal drugs are
fluconazole (3) [16, 17], itraconazole (4) [18], ravuconazole
(5) [19], voriconazole (6) [20-22] and posaconazole (7) [23].
Some triazole derivatives are considered as angiotensin II
receptor antagonists [24-27].
Furthermore, various 1,2,4-triazole derivatives are reported as insecticides [28], antiasthmatics [29], anticonvulsants [30], antidepressants [31], anti-inflammatory [32], insecticidal [33] and plant growth regulators [34]. In addition,
compounds having triazole moieties, such as vorozole (8),
letrozole (9), and anastrozole (10) are found to be very effective aromatase inhibitors, which could prevent breast cancer
[35-37]. 1,2,4-triazole moiety is reported to interact strongly
with heme iron, and aromatic substituents on the triazole are
very effective in interacting with the active site of aromatase
[38, 39].
In fact, there are various drugs, which contain 1,2,4triazole nucleus viz., triazolam (11) [40], alprazolam (12)
[41], etizolam (13) [42] and furacylin [43]. Many sulfur
containing heterocycles are quite promising with several
practical applications. The mercapto and thione substituted
1,2,4-triazole derivatives possess antibacterial [44-47], antifungal [48-50], antitubercular [51], antimycobacterial [52],
anticancer [53, 54], diuretic [55, 56] and hypoglycemic [57]
properties.
2013 Bentham Science Publishers
Maddila et al.
Me
N
N
O 2N
R2
Me
NH2
N
O
Cl
R1
R3
1
2
F
OH
N
N
N
3
N
O
N
Cl
N
O
Me
OH
N
N
CN
FS
Me
OH
N
NF
F
6
F
5
N
Me
Cl
Me
O
N
N
O
Cl
OH
Me
Me
Cl
N
N
N
NC
N
Me
Me
Me
N
N
N
Cl
8
Cl
Cl
9
Me
Me
CN
10
Triazole Derivatives
H 3C
Cl
N
N
N
Cl
H 3C
N
Cl
N
13
12
11
Ribavirin (14), a substituted 1,2,4-triazole-3-carboxamide
possesses antiviral activity against RNA and DNA viruses
[58]. It inhibits the replication of HIV in human T lymphocytes [59]. Isopropylidene ribavirin (15) acts as an inhibitor
of several viruses [60]. Trisubstituted 1,2,4-triazoles (16)
reportedly exhibit potent antiviral activity against efavirenzand nevirapine-resistant viruses [61]. While, diarylthiazolotriazole (17) demonstrates selectivity against human
COX-1 and COX-2 enzymes [62], Maraviroc [63] (18) is
known as an antiretroviral drug in the treatment of HIV infection. Deferasirox [64] (19) is a rationally-designed oral
iron chelator, which is used to reduce chronic iron overload
in patients and other chronic anemias.
Cl
N N
In addition to these, triazoles fused with pyridines, pyridazines, pyrimidines, pyrazines and triazines exhibit diverse
applications in the field of medicine, agriculture and industry. The pyrazolo triazoles (20) are found to have analgesic
activity [65].
OH
N
OH
19
HN N
HO
N
N
RO
OH
14
N
S
(
)
N
R'
N
17
Ar'
NH2
R
16
15
Ar
R2
R1
N
N
N
N
H
N
N N
Me
20
CH2CH2OH
HO
CONH2
CONH2
Me
N N
695
18
N
X
Maddila et al.
Ph
N N
i
Et
Me
O
Et
H
N
N
H
Ph
Me
NH2
Ph
N N
ii
Me
Me
N
H
NH2
Ph
H
N
N N
i
Ph
N
Ph
(i)
Eqn. 2
O
H
N
H
H
N
HCONH2
R
N N
i
RNHNH2.HCl
HCONH2
Eqn. 3
(i)
NH2
N
N
H
H
NHNH2 +
EtO
N CN
(i) Et3N
N
N
H
N
Eqn. 4
Triazole Derivatives
H
N
O
NH2
O
N
H
R
NH
N N
R HN N
697
Eqn. 5
NH
R
NH
NH
i
X
N
H
NH2 +
HN NH
ii
NH HN
ii
N NH
R
R
Eqn. 6
N NH
O
R
N
H
NH2.
PhSO3H + ArCN
Ar
N NH
R
Ar
NH2 O
(i)
Eqn. 7
NH
Ph
N
H
H
N
Me
O
Me
N N
+
Cl
OEt
HO
Ph
Eqn. 8
R2
H
N
Maddila et al.
N N
NH2
+ R NCS
R HN
R2
N N
+
R1 HN
NH2
NH2
Eqn. 9
O
O
N N
NCS
NHNH2
+
R'
SH
R
R'
Eqn. 10
N
H
HN
N N
NH
R
OS
ii
SCH3
SH
N
NH2
Eqn. 11
N N
O
Ar
Ar
H
N
N
H
S- K +
SH
N
HN
S
N
N
Eqn. 12
NH
Ph
N N
Ph
Ph
OO
Ph
N
Ph
Eqn. 13
(i) PhN=PNHPh
S
H2N
N
N
H
H
(i) RCOOH /
NH2
N N
i
R
SH
N
NH2
Eqn. 14
N N
Ph
O
Ph
N
H
. PhSO H
3
N
NHCOPh
ii
N N
Ph
i
NNHCHO
H
N
Ph
N
H
ii
N
NHCOPh
Ph
O
Eqn. 15
Triazole Derivatives
N NH
S Me
NH
N
H
NH2
+
R'
OMe
N
H
NH2 +
(i) CH2Cl2 /
R'
Eqn. 16
N N
i
N
H
OMe
ii
N
R
crowave irradiation (Eqn. 22). Kidwai et al. [125] have reported a new antifungal 1,2,4-triazole derivatives from substituted hydrazide using various solid supports under microwave irradiation. Several potentially bioactive 1,2,4-triazole
derivatives were prepared adopting 1,3-cycloaddition methodology between different nitriles and 1-(chloroalkyl)azo
salts in the presence of SbCl5 as a Lewis acid [126-129].
The literature survey reveals that the cyclization of substituted thiosemicarbazides can occur in the presence of sodium carbonate [98,137-139], alkoxides [140, 141], sodium
hydroxide [142-147], triethylamine [148] or by their fusion
[149]. The bis(1,2,4-triazolyl) derivatives were prepared by
the
base
catalzsed
cyclodehydration
of
bis(thiosemicarbazide) derivatives [150, 151] (Eqn. 26).
However, the cyclization of 1,4-disubstituted thiosemicarbazides in acidic medium has also been a concept, which
attracted overwhelming interest. In this case the product was
found to be thiadiazole derivative instead of triazole [152,
HN NH
RCN
N N
R
R
N
NH2
HN NH
N
H
Eqn. 18
N
C
H
CH3
Eqn. 17
NH
NH
.HI
699
N N
N
R
Eqn. 19
Maddila et al.
N N
i
ArCN
Ar
Ar
N
NH2
ArCHO
Eqn. 20
ii
ArCN
Ar
N N
Ar
Ar
N N
(i) NH2OH.HCl /
Ar
N
NH2
O / MW
N
Me
Eqn. 21
O
1
NH2
N
H
HN N
R CN
R2
O
H2N
H
N
N
H
(i) OH
Eqn. 22
N N
Ph
HO
Ph
N
Ph
Ph
Eqn. 23
N
Me
H
N
NH
N N
N
H
MeS
S
Me
(i) Ac2O
Eqn. 24
O
N
H
H 2N
H
N
Ph
i
N N
Ph
OH
Eqn. 25
(i) HCO2H
S
RHN
(i) OH
N
H
-
H
N
H
N
( )n
O
S
N
H
N NH
HN N
i
NHR
N
R
( )n
R
Eqn. 26
Triazole Derivatives
HN N
S
H 2N
N
H
NH2 + PhCOCl
S
O
S
N
H
N
H
NH2
+ CF3COOH
S
R
N
H
Ph
N
Ph
701
N
H
Eqn. 27
HN N
H
N
CF3
CF3
(i)
Eqn. 28
O
O
Ar
N C S
NH
HN
NHAr
SNa
NaS
O
ii
ArHN
H2N
NH2
NH
HN
iii
NH
HN
NH
HS
HN
NHAr
ArHN
S
N N
N N
Ar
Ar
Eqn. 29
HN N
i
R
SH
SH
Eqn. 30
O
N
H
Cl
H
N
Cl
Maddila et al.
NH2
N N
i
Cl
SH
N
H
Cl
(i) NaOH
NH NH2
N
S
HN NH
+ NH4SCN
Eqn. 31
NH2
S
O
ii
N NH
(i) HCl /
(ii) NaOH /
Ph
HN
NH
SH
N
HN N
ii
NHCOPh
Eqn. 32
N NH
H 2N
N
H
HO
OS
NHCOPh
N
HN N
iii
H3C
NHCOPh
S
Ph
N
H
HN N
EtO
N
H
NH2 +
Eqn. 33
NH.HCl
Ph
(i) pH>7
Ph
Ph
Eqn. 34
Triazole Derivatives
703
N N
HS
S
S
RHN
N
H
H
N
NH2.HCl
RHN
N
H
N
R
NH2.HCl
N N
NH
RHN
NH
(i)
Cl
NH2
NH2
Eqn. 35
R
S
1
N
H
N
R
N NH
NH2
N
R1
R
R
S
N
H
(i) OH
N
H
Eqn. 36
H
N
OEt
HN N
i
S
N
H
OH
N
H
Eqn. 37
S
Ph
NH2
NH2
N
H
HN N
N N
+
PhHN
N
Ph
(i) PhNC
CONHNHCSNHR
(CH2)n
( )n
CONHNHCSNHR
(i) OH
N NH
HN N
i
Eqn. 38
Eqn. 39
O
H 2N
N
H
N N
ii
N N
NH2
O O
(i) alc. FeCl3 (ii) FeCl2
H2N
+ RCHO
HO
N
H
Eqn. 40
The
reaction
of
thiosemicarbazide
with
Ncyanoguanidine in an acidic medium afforded 3,5-diamino1-thiocarbamoyl-1,2,4-triazole [198] (Eqn. 42). The treatment of hydrazide derivative of pyrrolyl ester with phenyl
isothiocyanate followed by cyclization of the resulting semicarbazide derivative produced 1,2,4-triazole [199] (Eqn. 43).
However, cyclocondensation of 1-benzoylsemicarbazide and
1-isonicotinylsemicarbazide with primary amines in the
presence of anhydrous zinc chloride gave 3,4,5-trisubstituted
1,2,4-triazoles [200] (Eqn. 44).
Maddila et al.
Me
S
R
N
H
N N
Ar
i
S
H 2N
H 2N
NH2
N
H
Ar
Me
(i) Cu(ClO4)2 / MeOH
H
N
RN
Eqn. 41
H
N
H2N
NR
H
N
NH
S
N
H
NH2
S
NH2
N N
H 2N
NHR
Eqn. 42
CONHNH2
i
N
N
S
N
ii
Ph
NH
CONHNHCSNHPh
Ph
N
Ph
Ph
Eqn. 43
NH
R
OO
N N
NH2
Eqn. 44
N N
N N
i
Ar
NHR1
R1
Ar
HN N
Ar
Ar
H2N NH2
(i) NaNH2
Ar
Ar
Eqn. 45
Triazole Derivatives
NNH2
H2N
N NH
NH2
H2N
N
O
(i) BrCN / KHCO3
N N
i
O
NHR
N
Eqn. 46
NNH2
NH2
705
COOH
N
2
(i)
Eqn. 47
H
N
H
N
N
H
N
H
NH2
N
HO
Eqn. 48
(i) N2H4.H2O
S
R
N NH
H
N
NH
NH
HO
NH2
H
N
N N
NH2
HS
N
R
NH
NH2
Eqn. 49
(i) NaOH
N
CF3
CF3
ii
N NH
iii
F 3C
H 2N O
N N
F 3C
NH
F3C
F3C
CF3
N N
CF3
iii
F3C
MeHN NHMe
N
Me
CF3
Eqn. 50
R'
F15C7
R'
R'
F15C7
ii
NO
+
OO
F15C7
N
OH NHR"
R'
N
F15C7
(i) hv, 254 nm (ii) R"NH2
similar reaction has also transpired with aniline hydrochloride in pyridine [211]. The fluorinated 1,2,4-oxadiazoles in
the presence of methylamine or propylamine on irradiation
in methanol or acetonitrile led to the corresponding fluorinated 1-methyl or 1-propyl-1,2,4-triazoles [212] (Eqn. 51).
The rearrangement of 1,3,4-thiadiazoles to triazoles was
similar to that of oxa analogs, but the former were less reliable, partly because they require higher temperatures below
which by-products were favored. Thus, 2-methylamino-
N
N
R"
Eqn. 51
Maddila et al.
N N
N NH
i
NHMe
N
Me
Eqn. 52
Ar
Ar
N N
N N
i
ArHN
N N
Ar
(i) NaOEt
Eqn. 53
R1
N NHR1
N N
Ph
Cl
ii
N NHR1
R2
iii
R
NH
H
N
R2
Eqn. 54
R
Cl
CO2Me
- +
N N C CO2Me
ii
N N
R1
CO2Me
Eqn. 55
R2
NNHR2
1
Cl
R CN
(i) Yb(OTf)3
N N
i
1
Eqn. 56
Triazole Derivatives
O O
O
S
( )n
O O
O
( )n
OMe
NHNH2
ii
R
O O
O
S
( )n
NHNHCS K +
S
R
O
( )n
iv
iii
R
R
O
SH
( )n
( )n
SH
S
N
SH
NH2
H+
Eqn. 57
NOH
O
NOH
O
N
S
OMe
H
N
ii
OMe
O
NHNH2
iii
O
NOH
O
O
- +
NHNHCSK
S
R
v
iv
NOH
O
S
R
N N
N
NH2
vii
O
N N
S
SH
vii
O
NOH
O
N N
vi
O
SH
R
NOH
O
SH
vii
N
NH2
SH
N N
O
N N
SH
N N
O
SH
(i) N2H4.H2O / Pyridine / EtOH (ii) NH2OH.HCl / EtOH (iii) CS2 / KOH /
(iv) AcOH (v) N2H4.H2O (vi) H+ (vii) -CD / H2O
Eqn. 58
707
Maddila et al.
azepinone was obtained instead of the expected acid hydrazide. However, the desired heterocycles were prepared by
protecting the carbonyl group as oxime derivative followed
by treatment of potassium dithiocarbazate with respective
reagents. The deprotection was effected with -cyclodextrin
in the presence of iodoxybenzoic acid [224] (Eqn. 58).
Apart from these, phenacylsulfonylacetic acid methyl ester was also used to develop bis-heterocycles, 1,2,3selenadiazolyl/thiadiazolyl/diazaphosphonyl
oxadiazoles,
thiadiazoles and triazoles. The -ketomethylene group in the
former compound was exploited for the construction of selenadiazole, thiadiazole and diazaphosphole rings and ester
functionality for thiadiazole, oxadiazole and triazole moieties
[225] (Eqn. 59). In addition to these, novel sulfone linked bis
heterocycles pyrazolines in combination with thiadiazoles,
oxadiazoles and triazoles were prepared by appropriate functionalization of olefin and ester moieties in Estyrylsulfonylacetic acid methyl ester and aroylethenesulfonylacetic acid methyl ester. Thus, 1,3-dipolar cycloaddition of diazomethane to the latter compounds resulted in (4phenyl-4,5-dihydro-1H-pyrazole-3-sulfonyl)acetic
acid
methyl ester and (3-aroyl-4,5-dihydro-1H-pyrazole-4sulfonyl)acetic acid methyl ester. The ester group in these
compounds through potassium salt of acid hydrazides was
O
CONCLUSION
Triazoles have pronounced biological and medicinal significance, and occupy unique place in the organic chemistry
and our lives. With the enormous literature continuously
accumulating over the years, the chemistry of triazoles sustains to be a promising field in the years to come. The multipurpose synthetic applicability and biological activity of
these heterocycles will facilitate the medicinal chemists to
plan, design and implement new approaches towards the
discovery of novel drugs.
H2NOCHN N
OMe
O
OMe
ii
R
O
N
O
OMe
Se
N
R
O
iv
O
S
- +
NHNHCS K
S
vi
vii
R
O
N N
S
O
Se
N
NHNH2
Se
Se
iii
N N
S
S
SH
N
Se
N
R
O
SH
N N
S
N
Se
N
SH
NH2
Eqn. 59
Triazole Derivatives
ii
OMe
O
S
OMe
N
709
N
H
R
O
NHNH2
iii
NHNHCS K
N
H
N
H
iv
R
N
O
vi
N
Ar
S
O
O
O
Ar
O
i
Ar
OMe
O O
O O
O O
O
NHNH2
iii
Ar
Ar
O O
O O
O O
NHNHCS K+
S
N N
O
N
H
ii
OMe
N
H
iv
O O
Eqn. 60
N
H
N
H
SH
NH2
N
H
N
H
(i) CH2N2 / Et2O / Et3N (ii) N2H4.H2O / MeOH (iii) CS2 / KOH / EtOH
(iv) HCl (v) AcOH (vi) N2H4.H2O
N
N
SH
N
H
SH
O
SH
Ar
O O
vi
N N
O
S
SH
Ar
N
H
The authors confirm that this article content has no conflict of interest.
N N
N
N
H
CONFLICT OF INTEREST
O O
SH
NH2
Eqn. 61
from the University of KwaZulu-Natal in the form of postdoctoral bursaries to SM and RP.
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