Synthesis and anti-HSV-1 activity of new 1,2,3-triazole derivatives

Article abstract of DOI:10.1016/j.bmc.2011.02.007

In this work, a new series of arysulfonylhydrazine-1H-1,2,3-triazole derivatives were synthesized, and their ability to inhibit the in vitro replication of HSV-1 was evaluated. Among the 1,2,3-triazole derivatives, 1-[(5″-methyl-1″-(4?-fluorophenylamino)-

Full text of DOI:10.1016/j.bmc.2011.02.007

Bioorganic & Medicinal Chemistry 19 (2011) 1860–1865
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and anti-HSV-1 activity of new 1,2,3-triazole derivatives
Alessandro K. Jordão a, Vitor F. Ferreira a, Thiago M. L. Souza b, Gabrielle G. de Souza Faria a,
Viviane Machado b, Juliana L. Abrantes b,c, Maria C. B. V. de Souza a, Anna C. Cunha a,
⇑
a Universidade Federal Fluminense, Departamento de Química Orgânica, Programa de Pós-Graduação em Química, Outeiro de São João Baptista, 24020-141 Niterói,
Rio de Janeiro, Brazil
b Laboratório de vírus respiratórios e do sarampo/Brazilian National Influenza Center (NIC), Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brazil
c Laboratório de Estrutura e Regulação de proteínas, Programa de pós-graduação em Química Biológica, Instituto de Bioquímica Médica, UFRJ, Rio de Janeiro, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
In this work, a new series of arysulfonylhydrazine-1H-1,2,3-triazole derivatives were synthesized, and
their ability to inhibit the in vitro replication of HSV-1 was evaluated. Among the 1,2,
3-triazole derivatives, 1-[(500-methyl-100-(4000-fluorophenylamino)-1H-1,2,3-triazol-400-yl)carbonyl]-2-(40-
meth- ylphenylsulfonyl)hydrazine and 1-[(50-methyl-10-(200,500-dichlorophenylamino)-1H-1,2,3-triazol-
Received 16 December 2010
Revised 1 February 2011
Accepted 3 February 2011
Available online 2 March 2011
40-yl)carbonyl]-2-(phenylsulfonyl)hydrazine, with IC50 values of 1.30 and 1.26
lM, respectively,
displayed potent activity against HSV-1. Because these compounds have low cytotoxicity, their selectivity
indices are high. Under the assay conditions, they have better performance than does the reference com-
pound acyclovir. The structures of all of the compounds were confirmed by one- and two-dimensional
Keywords:
1,2,3-Triazole derivatives
Diazocompounds
Anti-HSV-1
1
NMR techniques (1H, 13C-APT, COSY-1H ꢀ 1H and HETCOR JCH) and by elemental analysis.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
The other viruses of the subfamily Alphaherpesvirinae3,6 include
Human herpesvirus 3 (Varicella zoster virus, VZV), Human herpes-
The Herpesviridae is a large family of DNA viruses that cause
diseases in animals, including humans. There are 25 types of
viruses within this family, and they are currently divided into
three subfamilies: Alphaherpesvirinae, Betaherpesvirinae, and
Gammaherpesvirinae.1 In particular, eight or more types of her-
pes viruses of the subfamily Alphaherpesvirinae are known to
cause frequent infections in humans. Infection with the herpes
virus is categorized into one of several distinct disorders on
the basis of the site of infection.2 For instance, herpes simplex
viruses 1 and 2 (HSV-1 and HSV-2), also known as Human her-
virus 4 (Epstein–Barr virus, EBV), Human herpesvirus 5 (Cytomeg-
alovirus, CMV), Human herpesvirus (Roseolovirus), Human
herpesvirus 7 (Roseolovirus), and Human herpesvirus 8 (Kaposi’s
sarcoma-associated herpesvirus, KSHV).
6
Most antiherpetic drugs in clinical use, such as acyclovir (ACV,
1), penciclovir (2), and ribavirin (3), are nucleoside analogues
(Fig. 1). However, cidofovir (4) is a phosphonate molecule derived
from cytidine.5–8 Nucleoside analogues, such as 1 and 2, are pro-
drugs, because they need to be phosphorylated before they become
effective. These compounds are selectively phosphorylated only
within virus-infected cells by viral thymidine kinase (TK).9,10 Addi-
tional phosphorylation by cellular enzymes leads to the production
of acyclovir or penciclovir triphosphate, both of which compete
with the natural nucleotide, dGTP, resulting in the selective inhibi-
tion of viral DNA polymerase. Incorporation of the triphosphate
into the growing DNA chain prevents continued extension of the
chain.9,10
The emergence of virus strains that are resistant to commonly
used anti-herpesvirus drugs is a problem in clinical settings, partic-
ularly in immunocompromised individuals undergoing HSV-1
infection.11–13 Alternative approaches, such as the clinical use of
non-nucleoside drugs, have been studied.14–17 Examples of non-
nucleoside inhibitors that have been proposed as candidate drugs
for the treatment of herpes virus replication have recently been
described (Fig. 2).14–17
pes viruses 1 and
2 (HHV-1 and HHV-2), commonly cause
recurrent infections affecting the skin, the mouth (gingivostoma-
titis), the lips (herpes labialis), the eyes (herpes keratitis), and
the genitals.2 Although HSV-1 is traditionally associated with
orofacial lesions, it may also cause genital infection. HSV-2 also
causes genital lesions1 that are classified as sexually transmitted
diseases (STD).3 Other syndromes related to these viruses in-
clude encephalitis, viral meningitis, neonatal herpes, and, in
immunocompromised patients, disseminated infection.4 Herpes
virus is generally transmitted by direct contact of the skin or
the mucous membranes of the mouth and genitals when the
sores are present or just before the sores appear (a process
known as viral shedding).5
⇑
Corresponding author. Tel.: +55 21 26292148; fax: +55 21 26292145.
E-mail address: annac@vm.uff.br (A.C. Cunha).
0968-0896/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2011.02.007

A. K. Jordão et al. / Bioorg. Med. Chem. 19 (2011) 1860–1865
1861
NH2
O
N
N
O
O
N
N
H2N
O
H
N
N
O
H
N
N
N
N
N
N
HO
HO
P
HO
O
H2N
N
H2N
HO
O
O
HO
OH
OH
OH
2
4
1
3
OH
Figure 1. Antiviral drugs in clinical use against herpes virus.
Me
Me
N
O
P
H
O
O
H
Me
O
OH
HO
N
H
N
O
3 Na
Me
O
Cl
O
O
S
O
N
H
6, PNU-181465
O
5
, BAS 38-4766
7, Foscarnet, PFA
N
S
Me
N
O
O
8
OMe
OMe
Figure 2. Non nucleoside inhibitors of herpes virus replication.
1,2,3-Triazole derivatives, which belong to an important
group of N-heterocyclic compounds, have been the subject of
extensive studies, because several biological properties, such as
antiplatelet,18,19 antipsychotic,20 tuberculostatic,21 antiophidic,22
and antiviral23,24 properties, have been associated with this class
of substances.
In addition, we investigated the effect of different substituents at-
tached to N-phenyl ring on biological activity (Scheme 2).
2. Results and discussion
2.1. Chemistry
Two general synthetic methods are available for the construc-
tion of 1,2,3-triazole rings: Huisgen’s [1,3]-dipolar cycloaddition
The synthesis of new arylsulfonylhydrazide-1,2,3-triazole
derivatives 9a–i is shown in Scheme 1. The ethyl N-substituted-
phenylamino-4-carbethoxy-1H-1,2,3-triazoles 10a–e were pre-
pared in moderate yields by the condensation of ethyl 2-diazoace-
toacetate with substituted phenylhydrazine hydrochlorides
according to the method outlined in our previous report.23 These
compounds were converted into corresponding carbohydrazides
11a–e on treatment with hydrazine hydrate in refluxing ethanol.24
The new class of triazoles 9a–i was prepared by the condensa-
tion of compounds 11a–e with suitable arylsulfonyl chlorides
12a–c in pyridine. The yields of these reactions (9a–i) are listed
in Table 1.
reactions25 (in particular, copper(I)-catalyzed cycloaddition26
)
and the intramolecular 1,5-electrocyclization of b-substituted
a
-diazocarbonyl compounds.27,28 The latter method is more flexi-
ble, because it uses readily available carbonyl compounds. With
this methodology, two pathways can be followed: (i) starting from
b-amino-
transfer reaction31,32 (pathway I) and (ii) starting from
carbonyl compounds,18 followed by -diazoimino formation29,33
a
,b-unsaturated ketones or esters,29,30 followed by a diazo
a-diazo-
a
(pathway II) (Scheme 1). The diazo donor reagents can be
3-diazo-1,3-dihydro-2H-indol-2-one28,34 and sulfonyl azides,35
such as tosyl azide, p-carboxylbenzenesulfonyl azide, and meth-
anesulfonyl azide.
Recently, we have published the design and synthesis of
N-amino-1,2,3-triazole derivatives and an evaluation of their
antiviral activity against Cantagalo virus (CTGV) replication in cell
culture. In this study, it was found that the compound 1-(4-fluoro-
phenylamino)-5-methyl-1H-[1,2,3]-triazole-4-carbohydrazide,24
exhibited a significant effect against CTGV. CTGV was the first
sample isolated during a poxvirus outbreak in 1999 in Rio de Ja-
neiro state, and it was characterized as a vaccinia virus (VACV)
strain.
As part of an ongoing research program on the synthesis of
new bioactive N-heterocycles by using diazocarbonyl com-
pounds,18–20,22,24 we herein report the synthesis and anti-HSV-1
evaluation of a family of 1,2,3-triazole derivatives 9a–i bearing
an arylsulfonylhydrazide function at position C-4 of the azolic ring.
2.2. Materials and methods
2.2.1. Cells and virus
African green monkey kidney cells (Vero) were cultured in
Dulbecco’s Modified Eagles Medium (DMEM) with 5% fetal bovine
serum (FBS), 100 U/mL penicillin and 100 lg/mL streptomycin and
then incubated at 37 °C in 5% CO2. Vero cells were infected with
HSV-1 to obtain virus stock at a multiplicity of infection36 (MOI)
of 0.1 at 37 °C for 1 h. At 48 h post-infection (p.i.), cell supernatants
were centrifuged and stored at ꢁ70 °C.
2.2.2. Cytotoxicity assay
Monolayers of Vero cells in 96-multiwell plates (104 cells/well)
were treated with different concentrations of the test compounds

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A. K. Jordão et al. / Bioorg. Med. Chem. 19 (2011) 1860–1865
Equation 1
Pathway
I
O
R
H
N
R1
Me
R1OC
H3C
N
N
O
N
NaH
+
MsNH2
N
Me
R1
Ms N3
N
N
R
R
Equation 2
Pathway
II
O
H
O
N
O
O
N
R2
R2
N
R3NH2
R2
H
N
N
N2
N
R3
R3
R = Bn and R1 = OEt
R = Bn and R1 = Me
R2 = H and R3 = 4-FC6H5
R2 = Thiophene-2-yl and R3 = BrCH2CH2
R = n-Bu and R1 = OEt R2 = 2,5-Me2-furan-3-yl and R3 = C6H5
Scheme 1. Methods for preparing triazoles from -diazoimines.
a
H
N
SO2Cl
O
O
O
O
12a, R4 =H
O
S
N
H
N
N
N
O
12b, R4 = Me
12c, R4 = OMe
N
NHNH2
Me
Me
H
N
N
Me
NH2NH2.H2O (80%)
N
N
N
R3
R1
R1
R1
N
N
N
pyridine
4-5h, 25ºC
EtOH, 2h, Δ
H
R4
H
R2
R2
R2
R3
R3
R3
10a,
R1= R2 = R3= H
11a
, R1= R2 = R3= H
10b, R1=R3= H and R2= F
10c, R1=R3= H and R2= Cl
10d, R1=R3= H and R2= Br
11b, R1=R3= H and R2= F
11c, R1=R3= H and R2= Cl
11d, R1=R3= H and R2= Br
9a, R1= R2 = R3= R4 = H
9b
, R1= R2 = R3= H and R4 = Me
9c, R1=R2= R3= H and R4 = OMe
9d, R1= R3= H, R2 = F and R4 = Me
9e,
10e,
R1=R3= Cl and R2= H
11e,
R1=R3= Cl and R2= H
R1=R3= R4 = H and R2= Cl
9f, R1=R3= R4 = H and R2= Br
9g, R1=R3= H, R2= Br and R4 = Me
9h, R1=R3= H, R2= Br and R4 = OMe
9i,
R1=R3= Cl and R2= R4 = H
Scheme 2. Synthetic pathways used for the preparation of 9a–i.
for 72 h. Then, XTT (2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-
tetrazolium-5-carboxanilide) was added to each well at a final con-
centration of 2.5 mg/mL in the presence of phenazine methosulfate
compounds. After a 24 h incubation period, HSV-1-infected cells
were lysed, the supernatant of these cells was harvested and tit-
tered as described in the previous paragraph.37 Acyclovir was used
as a positive control. The 50% inhibitory concentration (CC50) was
calculated by linear regression analysis of the dose-response
curves obtained from the data.
(PMS) at 32 lg/mL. After a 4 h incubation period, the optical den-
sity was measured using a spectrophotometer with 492-nm test
and 620-nm reference wavelengths. For comparison, acyclovir
was used as a positive control. The 50% cytotoxic concentration
(CC50) was calculated by linear regression analysis of the dose-
response curves obtained from the data.
2.3. Anti-HSV-1 activity
The 1,2,3-triazole derivatives 9a–i were evaluated for their
2.2.3. Anti-HSV-1 assays
inhibitory effect on HSV-1 (Table 2). Of the nine tested compounds,
five inhibited virus replication by more than 70% at 50 lM after
Vero cells (104 cells/well) in 96-well plates were infected with
HSV-1 at 100 CCID50/well for 1 h. After that, virus inoculum was re-
72 h post-infection. The bioactive compounds 9a (R1 = R2 = R3 =
R4 = H), 9d (R1 = H, R2 = F, R3 = H and R4 = Me), 9g (R1 = H, R2 = Br,
R3 = H and R4 = Me), 9h (R1 = H, R2 = Br, R3 = H and R4 = OMe), and
9i (R1 = Cl, R2 = H, R3 = Cl and R4 = H) inhibited HSV-1 replication
by 79%, 88%, 69%, 77%, and 71%, respectively. The positive control
acyclovir (ACV) inhibited 95% of HSV-1 replication under these
experimental conditions.
The cytotoxicity and antiviral potency of the most-active tria-
zoles 9a, 9b, 9d, 9h, and 9i were evaluated (Table 3). These azo-
compounds were less cytotoxic (CC50 = 1512, 863, 1266, 971, and
moved, cells were washed and a medium containing 50 lM of the
test compounds was added. After incubation for 72 h, XTT/PMS
solution was added to each well to measure the ability of the com-
pounds to inhibit the HSV-1-induced cytopathic effect, as de-
scribed above.37
To determine the IC50 values of the test compounds, Vero cells
in a 6-well plates were infected with HSV-1 at an MOI of 5 for
1 h at 37 °C. After this period of time, cells were washed and
treated with different concentrations of the most effect test

A. K. Jordão et al. / Bioorg. Med. Chem. 19 (2011) 1860–1865
1863
Table 1
Table 3
Yields and mp for arylsulfonylhydrazide-1,2,3-triazoles 9a–i
Cytotoxicity, anti-HSV-1 activity, and selectivity index in Vero cells for triazole
derivatives 9a, 9d, 9h, and 9i
H
O
O
SIc
80
974
26
932
869
a
b
Compounds
R1
R2
R3
R4
CC50
(l
M)
IC50 (lM)
N
O
S
N
H
N
9a
H
H
H
Cl
—
H
F
Br
H
—
H
H
H
Cl
—
H
1512 34
1266 62
971 23
1174 52
860 25
19 0.02
1.3 0.04
37 3.0
1.26 0.03
0.99 0.02
N
Me
H
9d
9h
9i
Me
OMe
H
N
R1
N
R4
ACV
—
9a-i
R2
Acyclovir was used as a positive control. The mean values standard deviations are
R3
representative of three independent experiments.
a
CC50: cytotoxic concentration (lM) or concentration required to reduce the
Compounds
R1
R2
R3
R4
H
Me
OMe
Me
H
Mp (°C)
Yield (%)
viability of host cells by 50%. The cytotoxicity was determined by XTT assay and the
anti-HSV-1 activity by viral plaque number reduction assay.
9a
9b
9c
9d
9e
9f
9g
9h
9i
H
H
H
H
H
H
H
H
Cl
H
H
H
F
Cl
Br
Br
Br
H
H
H
H
H
H
H
H
H
Cl
180–182
207–215
187–190
208–210
188–191
185–193
207–208
167–169
235–238
87
73
67
60
47
69
78
93
83
b
IC50: 50% inhibitory concentration, defined as the concentration (lM) that
inhibited 50% of viral plaque formation when compared to untreated controls.
c
SI: selectivity index is the ratio between CC50 and IC50 values.
H
Me
OMe
H
activities against HSV-1 replication in cell culture. Among these
N-heterocyclic derivatives, compounds 9d and 9i were the most
promising molecules with potent anti-HSV-1 activity. These com-
pounds exhibited lower cytotoxicity and higher selectivity indices
than did the reference compound acyclovir.
These 1,2,3-triazole analogues, 9d and 9i, represent promising
structures for the development of new compound analogues with
anti-HSV-1 activity and for future in vivo analysis.
Table 2
Antiviral activity for 1,2,3-triazole derivatives 9a–i
H
N
O
O
O
S
N
H
N
N
Me
H
N
4. Experimental section
R1
N
Melting points were determined with a Fisher-Johns instrument
and are uncorrected. Infrared (IR) spectra were recorded on an ABB
FTLA2000-100 spectrophotometer in KBr pellets. NMR spectra, un-
less otherwise stated, were obtained in Me2SO-d6 or CDCl3 by using
a Varian Unity Plus 300 MHz spectrometer. Chemical shifts (d) are
expressed in ppm and the coupling constants (J) in Hertz. Column
chromatography purification was performed on silica gel flash
from Across. Reactions were routinely monitored by thin-layer
chromatography (TLC) on Silica Gel pre-coated F254 by using Merck
plates. Microanalyses were performed on a Perkin–Elmer Model
2400 instrument, and all values were within 0.4% of the calcu-
lated compositions.
R4
9a-i
R2
R3
Compounds
R1
R2
R3
R4
% of inhibition of virus
yielda (HSV-1)
9a
9b
9c
9d
9e
9f
9g
9h
9i
H
H
H
H
H
H
H
H
Cl
—
H
H
H
F
Cl
Br
Br
Br
H
H
H
H
H
H
H
H
H
Cl
—
H
79 2.3
37 1.2
54 3.2
88 2.0
57 4.3
31 1.5
69 2.2
77 4.5
71 3.9
95 1.2
Me
OMe
Me
H
H
Me
OMe
H
4.1. Chemistry
ACV
—
—
a
The experimental concentrations of triazole derivatives 9a–i were 50
ACV concentration was 50 M. Results are presented as means of triplicate
experiments. ACV-acyclovir has been included for comparison purposes.
lM and
4.1.1. General procedure for the preparation of the 1,2,3-triazole
derivatives 9a–i
l
To a stirred solution of 4-carbohydrazide-1,2,3-triazole deriva-
tives 10a–e (1 mmol) in pyridine (10 mL), the desired aryl sulfonyl-
chlorides (1.2 mmol) were added at 0 °C. The resulting mixture
was stirred at room temperature for 4–5 h. After this period, the
reaction mixture was diluted with 1 M HCl and extracted with
ethyl acetate (4 ꢀ 25 mL). The combined layers were washed with
sodium bicarbonate solution, filtered, and dried over anhydrous
Na2SO4. Evaporation of the solvent under vacuum produced the
crude products that were purified by column chromatography
employing EtOAc/hexane mixture as eluent giving:
1174
860 54
pounds, 9d and 9i, with IC50 values of 1.30 and 1.26
tively, displayed potent activity against HSV-1. Selective index
(SI) values, which represent the in vitro antiviral potency and
safety of a candidate antiviral drug, of 9d and 9i are comparable
to the ACV SI (Table 3). The antiviral activity of these compounds
is comparable to that of other molecules studied by our group36
and described elsewhere.37
l
M) than was acyclovir, which presented
M, under our assay conditions.38 Only two of these com-
M, respec-
a CC50 of
l
l
4.1.1.1. 1-[(50-Methyl-10-(phenylamino)-1H-1,2,3-triazol-40-yl)-
These results strongly suggest that compounds 9d and 9i could
be considered as promising candidates for the development of new
derivatives with anti-HSV-1 activity and for additional studies con-
cerning the antiviral activity of this group of compounds.
carbonyl]-2-(phenylsulfonyl)hydrazine 9a.
As a white solid by
condensation of 11a with benzenesulfonyl chloride. IR (KBr) mmax
(cmꢁ1) 3248 (N–H), 1685 (C@O); 1H NMR (300.00 MHz, DMSO-
d6) d 2.38 (s, 3H, CH3), 6.42–6.45 (m, 2H), 6.89–6.94 (m, 1H),
7.21–7.27 (m, 2H), 7.54–7.59 (m, 2H), 7.65–7.68 (m, 1H), 7.84–
7.87 (m, 2H), 10.12 (br s, 1H, N–H) ppm. 13C NMR (75 MHz,
DMSO-d6) d 8.0 (CH3), 112.9 (C-20 and C-60), 121.2 (C-40), 127.6
(C-30 and C-50), 128.9 (C-200 and C-600), 129.5 (C-300 and C-500),
3. Conclusion
In summary, a new series of arysulfonylhydrazide-1,2,3-tria-
zoles, 9a–i, have been synthesized and evaluated for their antiviral

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A. K. Jordão et al. / Bioorg. Med. Chem. 19 (2011) 1860–1865
133.0 (C-400), 135.6 (C-4 or C-5), 138.1 (C-4 or C-5), 146.1 (C-10),
159.9 (C@O) ppm. Anal. Calcd for C16H16N6O2S: C, 51.60; H, 4.33;
N, 22.57. Found: C, 51.57; H, 4.67; N, 21.48.
7.84–7.87 (m, 2H), 10.30 (br s, 1H, N–H) ppm. 13C NMR (75 MHz,
DMSO-d6) d 7.8 (CH3), 112.7 (C-40), 115.0 (C-20 and C-60), 127.5
(C-30 and C-50), 128.8 (C-200 and C-600), 132.1 (C-300 and C-500),
135.6 (C-400), 137.9 (C-4 or C-5), 139.3 (C-4 or C-5), 139.3 (C-100),
145.3 (C-10), 159.7 (C@O) ppm.
4.1.1.2. 1-[(500-Methyl-100-(phenylamino)-1H-1,2,3-triazol-400-yl)-
carbonyl]-2-(40methylphenylsulfonyl)hydrazine 9b. As a white
solid by condensation of 11a with p-tolylsulfonyl chloride chloride.
4.1.1.7.
triazol-400-yl)carbonyl]-2-(40-methylphenylsulfonyl)hydrazine
9g. As a white solid by condensation of 11d with p-tolylsulfo-
1-[(500-Methyl-100-(4000-bromophenylamino)-1H-1,2,3-
)
IR (KBr) mmax (cmꢁ1 3306 (N–H); 1685 (C@O); 1H NMR
(300.00 MHz, DMSO-d6) d 2.28 (s, 3H, CH3), 2.38 (s, 3H, CH3),
6.43–6.46 (m, 2H), 6.90–6.95 (m, 1H), 7.22–7.27 (m, 2H), 7.36 (d,
2H, J = 8.2), 7.74 (d, 2H, J = 8.5), 10.12 (br s, 1H, N–H) ppm. 13C
NMR (75 MHz, DMSO-d6) d 7.9 (CH3), 20.9 (CH3), 112.8 (C-20 and
C-60), 121.4 (C-40), 127.6 (C-2’’ and C-6’’), 129.2 (C-30 and C-50),
129.4 (C-300 and C-500), 135.5 (C-100), 136.4 (C-4 or C-5), 137.8 (C-4
or C-5), 143.2 (C-400), 145.9 (C-10), 146.1 (C-3’’ and C-5’’), 159.8
(C@O) ppm. Anal. Calcd for C17H18N6O3S: C, 52.84; H, 4.70; N,
21.75. Found: C, 53.55; H, 5.09; N, 20.98.
nyl chloride. IR (KBr) mmax (cmꢁ1) 3301 (N–H); 1678 (C@O); 1H
NMR (300.00 MHz, DMSO-d6) d 2.28 (s, 3H, CH3), 2.38 (s, 3H,
CH3), 6.42 (d, 2H, J = 8.9), 7.36 (d, 2H, J = 8.2), 7.41 (d, 2H, J = 8.9),
7.74 (d, 2H, J = 8.2), 10.28 (br s, 1H, N–H) ppm. 13C NMR
(75 MHz, DMSO-d6) d 7.8 (CH3), 20.9 (CH3), 112.7 (C-40), 114.9
(C-20 and C-60), 127.5 (C-200 and C-600), 129.2 (C-300 and C-500),
132.1 (C-30 and C-50), 135.6 (C-100), 136.4 (C-4 or C-5), 137.8 (C-4
or C-5), 143.1 (C-400), 145.3 (C-10), 159.7 (C@O) ppm. Anal. Calcd
for C17H17BrN6O3S: C, 43.88; H, 3.68; N, 18.06. Found: C, 44.07;
H, 4.01; N, 17.40.
4.1.1.3. 1-[(500-Methyl-100-(phenylamino)-1H-1,2,3-triazol-400-yl)-
carbonyl]-2-(40methoxylphenylsulfonyl)hydrazine 9c.
As a
white solid by condensation of 11a with p-methoxybenzenesulfo-
nyl chloride. IR (KBr) mmax (cmꢁ1) 3236 (N–H); 1675 (C@O); 1H
NMR (300.00 MHz, DMSO-d6) d 2.28 (s, 3H, CH3), 3.81 (s, 3H,
OCH3), 6.42–6.45 (m, 2H), 6.89–6.94 (m, 1H), 7.08 (d, 2H, J = 8.9),
7.21–7.27 (m, 2H), 7.78 (d, 2H, J = 8.9), 9.81 (br s, 1H, N–H),
10.12 (br s, 1H, N–H), 10.56 (br s, 1H, NH–C) ppm. 13C NMR
(75 MHz, DMSO-d6) d 8.0 (CH3), 55.6 (OCH3), 112.6 (C-200 and C-
600), 114.0 (C-300 and C-500), 121.5 (C-40), 129.4 (C-20 and C-60),
129.9 (C-30 and C-50), 130.7 (C-100), 135.6 (C-4 or C-5), 137.9 (C-4
or C-5), 146.1 (C-10), 159.8 (C-400), 162.6 (C@O) ppm. Anal. Calcd
for C17H18N6O4S: C, 50.74; H, 4.51; N, 20.88. Found: C, 50.15; H,
4.80; N, 19.92.
4.1.1.8.
3-triazol-400-yl)carbonyl]-2-(40-methoxylphenylsulfonyl)hydra-
zine 9h. As a white solid by condensation of 11d with
1-[(500-Methyl-100-(4000-bromophenylamino)-1H-1,2,
p-methoxybenzenesulfonyl chloride. IR (KBr) mmax (cmꢁ1) 3231
(N–H); 1684 (C@O); 1H NMR (300.00 MHz, DMSO-d6) d 2.28 (s,
3H, CH3), 2.38 (s, 3H, CH3), 6.42 (d, 2H, J = 8.8), 7.08 (d, 2H,
J = 9.0), 7.41 (d, 2H, J = 8.8), 7.78 (d, 2H, J = 9.0), 9.81 (br s, 1H,
N–H), 10.31 (br s, 1H, N–H), 10.57 (br s, 1H, N–HC) ppm. 13C
NMR (75 MHz, DMSO-d6) d 7.9 (CH3), 55.6 (CH3), 112.8 (C-40),
114.0 (C-20 and C-60), 115.0 (C-300 and C-500), 129.9 (C-200 and
C-600), 130.7 (C-100), 132.1 (C-30 and C-50), 135.7 (C-4 or C-5),
137.8 (C-4 or C-5), 145.3 (C-10), 159.7 (C-400), 162.6 (C@O) ppm.
Anal. Calcd for C17H17BrN6O4S: C, 42.42; H, 3.56; N, 17.46. Found:
C, 42.97; H, 3.84; N, 17.70.
4.1.1.4. 1-[(500-Methyl-100-(4000-fluorophenylamino)-1H-1,2,3-tria-
zol-400-yl)carbonyl]-2-(40methylphenylsulfonyl)hydrazine 9d. As
a white solid by condensation of 11b with p-tolylsulfonyl chloride.
4.1.1.9. 1-[(50-Methyl-10-(200,500-dichlorophenylamino)-1H-1,2,3-
IR (KBr) mmax (cmꢁ1
)
3218 (N–H); 1679 (C@O); 1H NMR
triazol-40-yl)carbonyl]-2-(phenylsulfonyl)hydrazine 9i.
As
(300.00 MHz, DMSO-d6) d 2.30 (s, 3H, CH3), 2.38 (s, 3H, CH3),
6.49 (dd, 2H, J = 9.0; 4.6), 7.08 (dd, 2H, J = 8.9; 8.8), 7.36 (d, 2H,
J = 8.1), 7.74 (d, 2H, J = 8.3), 10.10 (br s, 1H, N–H) ppm. 13C NMR
(75 MHz, DMSO-d6) d 7.8 (CH3), 20.9 (CH3), 114.6 (J = 8.3; C-20
and C-60), 115.9 (J = 8.3; C-30 and C-50), 127.5 (C-200 and C-600),
129.2 (C-300 and C-500), 135.6 (C-100), 136.4 (C-4 or C-5), 137.7 (C-4
or C-5), 142.4 (J = 2.3; C-10), 157.2 (J = 237.4; C-40), 159.7 (C@O)
ppm. Anal. Calcd for C17H17FN6O3S: C, 50.49; H, 4.24; N, 20.78.
Found: C, 50.26; H, 4.54; N, 20.15.
a white solid by condensation of 11e with benzenesulfonyl chlo-
ride. IR (KBr) mmax (cmꢁ1) 3248 (N–H); 1685 (C@O); 1H NMR
(300.00 MHz, DMSO-d6) d 2.28 (s, 3H, CH3), 6.02 (d, 1H, J = 2.5),
7.03 (dd, 1H, J = 2.5, 8.3), 7.49–7.58 (m, 3H), 7.63–7.68 (m, 1H),
7.86 (dd, 2H, J = 1.5, 7.3), 10.01 (br s, 1H, N–H), 10.24 (br s, 1H,
N–H), 10.68 (br s, 1H, NH–C) ppm. 13C NMR (75 MHz, DMSO-d6)
d 7.9 (CH3), 113.1 (C-60), 116.7 (C-50), 122.1 (C-40), 127.5 (C-200
and C-600), 128.5 (C-300 and C-500), 131.4 (C-30), 132.7 (C-20), 132.8
(C-400), 135.7 (C-4 or C-5), 138.2 (C-4 or C-5), 139.2 (C-10), 142.8
(C-100), 159.7 (C@O) ppm. Anal. Calcd for C16H14Cl2N6O3S: C,
43.55; H, 3.20; N, 19.04. Found: C, 43.37; H, 3.50; N, 19.36.
4.1.1.5. 1-[(50-Methyl-10-(400-chlorophenylamino)-1H-1,2,3-tria-
zol-40-yl)carbonyl]-2-(phenylsulfonyl)hydrazine 9e. As a white
solid by condensation of 11c with benzenesulfonyl chloride. IR
(KBr) mmax (cmꢁ1
)
3310 (N–H); 1677 (C@O); 1H NMR
Acknowledgments
(300.00 MHz, DMSO-d6) d 2.28 (s, 3H, CH3), 6.47 (d, 2H, J = 8.9),
7.28 (d, 2H, J = 8.9), 7.54–7.59 (m, 2H), 7.62–7.69 (m, 1H),
7.84–7.87 (m, 2H), 9.97 (br s, 1H, N–H), 10.12 (br s, 1H, N–H),
10.61 (br s, 1H, N–H) ppm. 13C NMR (75 MHz, DMSO-d6) d 7.8
(CH3), 114.5 (C-20 and C-60), 125.1 (C-40), 127.5 (C-30 and C-50),
128.8 (C-200 and C-600), 129.2 (C-300 and C-500), 132.8 (C-400), 135.6
(C-4 or C-5), 137.8 (C-4 or C-5), 139.4 (C-100), 144.9 (C-10), 159.7
(C@O) ppm.
This work was supported by the Brazilian agencies FAPERJ and
CNPq. Fellowships granted to UFF, by CAPES, CNPq-PIBIC and FA-
PERJ are gratefully acknowledged. The authors have declared no
conflict of interest.
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