Synthesis of novel sulfanilamide-derived 1,2,3-triazoles and their evaluation for antibacterial and antifungal activities

Article abstract of DOI:10.1016/j.ejmech.2010.07.031

A series of novel sulfanilamide-derived 1,2,3-triazole compounds were synthesized in excellent yields via 1,3-dipolar cycloaddition and confirmed by MS, IR and NMR spectra as well as elemental analyses. All the compounds were screened in vitro for their antibacterial and antifungal activities. Preliminary results indicated that some target compounds exhibited promising antibacterial potency. Especially, 4-amino-N-((1-dodecyl-1H-1,2,3-triazol-4-yl)methyl) benzenesulfonamide, N-((1-(2,4-dichlorobenzyl)- 1H-1,2,3-triazol-4-yl)methyl)-4- aminobenzenesulfonamide and 4-amino-N-((1-(2,4-difluorobenzyl)- 1H-1,2,3-triazol-4-yl)methyl) benzenesulfonamide were found to be the most potent compounds against all the tested strains except for Candida albicans (ATCC76615) and Candida mycoderma.

Full text of DOI:10.1016/j.ejmech.2010.07.031

European Journal of Medicinal Chemistry 45 (2010) 4631e4639
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis of novel sulfanilamide-derived 1,2,3-triazoles and their evaluation
for antibacterial and antifungal activities
*
Xian-Long Wang, Kun Wan, Cheng-He Zhou
Laboratory of Bioorganic & Medicinal Chemistry, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel sulfanilamide-derived 1,2,3-triazole compounds were synthesized in excellent yields via
1,3-dipolar cycloaddition and confirmed by MS, IR and NMR spectra as well as elemental analyses. All the
compounds were screened in vitro for their antibacterial and antifungal activities. Preliminary results
indicated that some target compounds exhibited promising antibacterial potency. Especially, 4-amino-N-
((1-dodecyl-1H-1,2,3-triazol-4-yl)methyl) benzenesulfonamide, N-((1-(2,4-dichlorobenzyl)- 1H-1,2,3-
triazol-4-yl)methyl)-4-aminobenzenesulfonamide and 4-amino-N-((1-(2,4-difluorobenzyl)- 1H-1,2,3-tri-
azol-4-yl)methyl) benzenesulfonamide were found to be the most potent compounds against all the tested
strains except for Candida albicans (ATCC76615) and Candida mycoderma.
Received 2 March 2010
Received in revised form
8 July 2010
Accepted 19 July 2010
Available online 24 July 2010
Keywords:
Sulfanilamide
1,2,3-Triazole
Antibacterial
Ó 2010 Elsevier Masson SAS. All rights reserved.
Antifungal
1,3-Dipolar cycloaddition
1. Introduction
drugs, or hybrid drugs, offer the possibility to overcome the current
resistance and reduce the appearance of new resistant strains [3].
The alarming rates of emerging and reemerging microbial
threats coupled with the growing emergence of antimicrobial
resistance in hospitals are major concerns to the public health and
scientific communities worldwide, especially in regard to multi-
drug-resistant Gram-positive bacteria such as methicillin-resistant
Staphylococcus aureus (MRSA) [1]. Thus, these trends have
emphasized the urgent need for new, more effective and safe
antimicrobial agents. Among the attractive approaches to achieve
this goal, the development of structurally new classes of antimi-
crobial agents with novel mechanism of action and the structural
modification or optimization of the existing agents by improving
both the binding affinity and spectrum of activity while retaining
bioavailability and safety profiles, have provoked special interest in
the realm of medical chemistry. However, the increasing preva-
lence of one such strategy that has been pursued in recent years
employs a combination of two different active fragments in one
molecule [2]. With this strategy, each drug moiety is designed to
bind independently to two different biological targets and
synchronously accumulate at both target sites. Such dual-action
Sulfonamides which were extensively employed as effective
antimicrobial antifolic agents for the prevention and cure of
bacterial infections in human biological systems as early as 70 years
ago, have aroused considerable interest in biology and medicine for
their diversified pharmacological activities including carbonic
anhydrase inhibitors [4], antifungal [5], antiviral [6], antitumor [7],
and anti-inflammatory ones [8] in recent years. Meanwhile,
sulfonamides have attracted increasing attention in the supramo-
lecular chemistry and supramolecular medicinal chemistry [9],
since it combined the features required for various biological
activities and the metal coordination through phenylamino and
sulfonyl amino groups. In particular, Ag-sulfadiazine has been
proved to be an effective topical antimicrobial agent, and to be of
significance in burn therapy, better than the free ligand or AgNO3.
Furthermore, sulfonamides combined with trimethoprin were
confirmed to considerably enhance their antibacterial efficacy by
a well known synergistic effect. For instance, sulfamethoxazole in
combination with trimethoprim is a very active pharmaceutical
compound and has been extensively used in clinic as the first
choice in the treatment of pneumonia and urinary tract bacterial
infections, toxoplasmosis [10] and pneumocystosis in HIV infected
patients [11]. Nevertheless, numerous researches have been still
focusing on the structure modification of sulfanilamide through the
phenylamino and sulfonyl amino groups to afford sulfanilamide-
* Corresponding author. Tel./fax: þ86 23 68254967, þ86 23 68254165.
E-mail address: zhouch@swu.edu.cn (C.-H. Zhou).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.07.031

4632
X.-L. Wang et al. / European Journal of Medicinal Chemistry 45 (2010) 4631e4639
based bioactive molecules in order to broaden their antimicrobial
spectrum of activity and improve their potency. Recently, a large
number of literatures manifested that the sulfanilamide moiety 1
retaining the structural eSO2NHe feature, which was incorporated
into nitrogen-containing aromatic heterocyclic groups with
different biological activities, could exhibit various pharmacolog-
ical activities or even enhance activities in comparison with the
sulfanilamide precursor [12]. Up to now, several sulfanilamide
derivatives (Fig. 1) bearing aromatic heterocyclic groups such as
isoxazole, thiazole, pyridazine, pyrimidine and so on at the N1-
position, have been successfully used in clinics owing to their
excellent antimicrobial activities.
2. Results and discussion
2.1. Chemistry
The synthetic route of target compounds was outlined in
Scheme 1. The target sulfanilamide-derived 1,2,3-triazoles 6aef
and 7aei were synthesized by using commercially available
acetaniline as starting material. The intermediate 3, prepared
according to the reference described [23], was upon N-alkylation
with 3-bromoprop-1-yne to yield the N-acetyl-protected sulfanil-
amide 4, and then the removal of the acetyl group in compound 4
by acidic hydrolysis with concentrated hydrochloric acid gave
propargyl sulfonamide 5. The 1,3-dipolar cycloaddition of propargyl
sulfonamide 5 with alkyl or aryl azides using catalytic amount of
copper sulfate and sodium ascorbate in t-BuOH/H2O at 60 ꢀC
afforded sulfanilamide-derived 1,4-disubstituted 1,2,3-triazoles
6aef and 7aei in moderate to good yields ranging from 68.6% to
90.2%.
Generally, the 1,3-dipolar cycloaddition of terminal acetylenes
with organic azides produces two isomers 1,4-disubstituted 1,2,3-
triazoles and 1,5-disubstituted ones. Numerous researches showed
that this type of cycloaddition by the copper(I) catalysis could
regioselectively yield 1,4-disubstituted 1,2,3-triazoles, the related
reaction mechanism has been systematically discussed in litera-
tures [24]. This catalytic process is involved in the Cu(I) acetylide
complex which coordinated the azide following by rearrangement
of the complex into a six-membered metallocycle and further into
the copper-metallated triazole and then the Cu-triazole complex
eventually released the free 1,4-disubstituted 1,2,3-triazole. In our
work all experiments showed that the Cu(I) ion could efficiently
affect the regioselectivity of 1,3-dipolar cycloaddition to produce
1,4-disubstituted 1,2,3-triazole derivatives, while 1,5-disubstituted
1,2,3-triazole ones were not almost obtained.
Furthermore, the experimental results also indicated that reac-
tion temperature, various substrates as well as the nature of solvent
exerted great influences on the 1,3-dipolar cycloaddition. In general,
lowering the reaction temperature would make the cycloaddition
reaction more stable and safe, which benefited the formation of
target products and diminished the complexity of the reaction.
However, temperature below 60 ꢀC would greatly decrease the
reactivity and make the reaction sluggish, thus leading to poor
yields. On the other side, the effect of solvent is another quite
important factor in the cycloaddition. Our observations indicated
that the mixture of t-BuOH/H2O or DMSO/H2O (V/V, 1/1) could give
good reactivity and excellent yields. Additionally, it was also found
that the structure of reaction substrates influenced efficiencies of
1,2,3-Triazole and its derivatives are an important class of
nitrogen-containing aromatic heterocyclic compounds, and have
attracted a great deal of interest due to their diverse biological
activities such as antitubercular [13], anti-HIV [14], antifungal [15],
antibacterial [16], and anticancer activities [17], along with the
introduction of ‘click chemistry’ for their easy synthesis. 1,2,3-Tri-
azole moiety is stable to metabolic degradation and capable of
hydrogen bonding, which could be favorable in binding of biomo-
lecular targets and increasing solubility [18]. Moreover, 1,2,3-tri-
azoles as attractive linker units which could connect two
pharmacophores to give an innovative bifunctional drugs, have
become increasingly useful and important in constructing bioactive
molecules and functional molecules [19]. Noticeably, the bio-
isosteric replacement between 1,2,3-triazole moiety and its bio-
isoster 1,2,4-triazole has received special attention in medical
chemistry, which represented an efficient concept for the discovery
and development of novel triazole drugs, significantly extending
the chemical space of triazole scaffolds possessing potent activities
or enhancing biological activities [20]. Additionally, many investi-
gations showed that the incorporation of alkyl chains and/or vari-
able aromatic substituents have an important effect on the
antimicrobial activities [21], especially some halogen-substituted
aromatic compounds such as 2,4-difluorobenzyl, 2,4-dichlor-
obenzyl, fluorobenzyl, chlorobenzyl and so on, were found to be
biologically important and could improve antimicrobial activities.
Based on all above considerations and as an extension of our
studies on the development of novel triazole antimicrobial agents
[22], we disclosed the synthesis of novel sulfanilamide-derived
1,2,3-triazoles 6aef and 7aei with different lengths of alkyl chains
or haloaryl compounds via a Cu(I) catalyzed 1,3-dipolar cycload-
dition. The synthesized compounds have also been screened for
their antibacterial and antifungal activities in vitro. Various func-
tional groups were introduced into the target compounds in order
to investigate their preliminary structure-activity relationships.
H3CO
N
NH2
O
S
N
N
H
Sulfamethoxypyridazine
NH2
O
N
S
O
S
NH2
O
N
N
O
H
O
O
S
N
N
H
S
Sulfafurazole
H2N
NH2
Sulfadimidine
NH2
O
NH2
O
N
Sulfanilamide
1
O
S
N
O
S
N
N
H
N
H
N
NH2
O
OCH3
O
Sulfathiazole
O
S
Sulfalene
N
N
H
Sulfaquinoxaline
O
Fig. 1. Structures of some sulfanilamide-derived drugs.

X.-L. Wang et al. / European Journal of Medicinal Chemistry 45 (2010) 4631e4639
4633
O
C
O
S
H
N
H
O
C
O
S
H3C
Br
N
H
N
iii
H3C
NH2
O
O
4
3
R3
ii
iv
R2
R1
i
O
O
H
v
2
H3C
C N
S
N
H
O
N3
vi
H2N
R3
v
5
N3(CH2)nCH3
Br(CH2)nCH3
R2
R1
vi
a R1 = H, R2 = H, R3 = H
b R1 = H, R2 = CH3, R3 = H
c R1 = H, R2 = H, R3 = NO2
d R1 = Cl, R2 = H, R3 = H
e R1 = H, R2 = Cl, R3 = H
f R1 = H, R2 = H, R3 = Cl
g R1 = Cl, R2 = H, R3 = Cl
h R1 = H, R2 = H, R3 = F
i R1 = F, R2 = H, R3 = F
O
S
O
N
N
R1
O
NH
N
N
(CH2)nCH3
O
S NH
N
N
a n = 4 b n = 5
c n = 7 d n = 9
e n = 11 f n = 15
R2
R3
7a-i
NH2
NH2 6a-f
Scheme 1. Synthetic route of novel sulfanilamide-derived 1,2,3-triazoles 6aef and 7aei. Reagents and conditions: (i) sulfurochloridic acid, 60 ꢀC; (ii) 30% NH3 aq., acetone, 0 ꢀC; (iii)
3-bromoprop-1-yne, acetone, 45 ꢀC; (iv) conc. HCl, EtOH, reflux; NaOH/H2O; (v) NaN3, CH3COCH3/H2O, reflux; (vi) sodium ascorbate (0.2 equiv), CuSO4$5H2O (0.1 equiv), t-BuOH/
H2O (1/1, V/V), 60 ꢀC.
cycloaddition significantly. For example, the short alkyl azides
would increase the reactivity of propargyl sulfonamide 5, while the
long alkyl azides showed lower reactivity.
SO2NHCH2 group in sulfanilamide-derived 1,2,3-triazoles 6aef and
7aei displayed larger shifts at 4.50e4.65 ppm in contrast to prop-
argyl sulfonamide 5 (
d 4.06 ppm) owing to the electron-with-
drawing character of 1,2,3-triazole group in the newly synthesized
compounds. In addition, the acetyl group results in slightly down-
field chemical shift at 4.17 ppm for the methylene protons of
SO2NHCH2 in N-acetyl-protected sulfanilamide 4 in comparision
2.2. Analysis of spectra
All the newly synthesized compounds were characterized by
MS, IR and NMR spectra as well as elemental analyses listed in the
experimental section. The spectral analyses were in accordance
with the assigned structures, and the mass spectra of target
compounds showed a major fragment of [M þ H]þ or [M þ Na]þ
according to their molecular formula.
with deprotected propargyl sulfonamide 5 (d 4.06 ppm).
2.2.3. 13C NMR spectra
The 13C NMR spectral analyses were consistent with the
assigned structures. No large differences were found in 13C chem-
ical shifts for the methylene carbon of SO2NHCH2 (
d 37.9e41.5 ppm)
moiety and triazole-CH2-R group ( 50.7e52.9 ppm) in all title
d
2.2.1. IR spectra
compounds. The SO2NHCH2 moiety in propargyl sulfonamide 5
gave slight upfield chemical shift at 31.6 ppm in contrast to N-
The IR spectra of propargyl sulfonamide 5 exhibited three
moderate absorption bands at 3404, 3339 and 3250 cmꢁ1, which
were respectively attributable to the stretching vibration of NeH in
the phenylamino and sulfonamide moiety and CeH in the terminal
alkyne (^CeH). The absorption bands of all synthesized sulfanil-
amide-derived 1,2,3-triazoles 6aef and 7aei associated with
functional groups appeared in the expected regions. Moreover, it
was found that all the vibration frequency of NeH in halobenzyl
1,2,3-triazoles was slightly shifted to higher wave numbers
compared with alkyl 1,2,3-triazoles (Table 1), which was mainly
responsible for the inductive effects of the electron-withdrawing
character of halogen- or nitro-substituted aryl moieties, especially
nitro-substituted sulfanilamide-derived 1,2,3-triazole 7c.
acetyl-protected sulfanilamide
4 (d 32.4 ppm). However, the
methylene carbon of triazole-CH2eR in aryl substituted 1,2,3-
Table 1
Some spectral data of synthesized compounds 5e7.
Compds. IR (
n
/cmꢁ1
)
1H NMR (
d
/ppm)
13C NMR (
d/ppm)
NeH
SO2NHCH2 triazole- SO2NHCH2 triazole-
CH2eR
CH2eR
5
3404, 3339
4.06
e
31.6
39.5
39.6
39.4
41.1
41.0
41.5
37.9
38.1
37.9
37.9
37.9
38.4
38.3
38.4
37.9
e
6a
6b
6c
6d
6e
6f
7a
7b
7c
7d
7e
7f
3353, 3308, 3275 4.61
3352, 3311, 3269 4.50
3353, 3308, 3271 4.61
3351, 3308, 3269 4.52
3352, 3310, 3269 4.50
3353, 3311, 3269 4.65
3360, 3269
3390, 3296
3383, 3330
3379, 3269
3380, 3332
3381, 3334
3366, 3336
3381, 3336
3379, 3335
4.44
4.33
4.45
4.35
4.31
4.50
5.51
5.48
5.76
5.67
5.50
5.49
5.65
5.53
5.53
51.0
50.8
50.8
50.7
50.7
50.8
52.7
52.9
51.8
51.6
51.8
51.8
51.6
51.9
52.1
2.2.2. 1H NMR spectra
The 1H NMR spectra revealed that two singlets at the region of
4.50e4.65 ppm and 4.31e5.76 ppm were assigned to the methylene
protons of SO2NHCH2 and triazole-CH2eR (R ¼ alkyl or aryl) moiety
in all title compounds respectively. In addition, the methylene
protons of triazole-CH2eR in aryl substituted 1,2,3-triazoles 7aei
appeared obvious downfield shifts in comparison with that in alkyl-
substituted 1,2,3-triazoles 6aef as a result of the strong electron-
withdrawing character of halogen-substituted aryl moieties in
compounds 7aei, as seen in Table 1. On the basis of the 1H NMR
spectra, it was also observed that all the methylene protons of the
4.45
4.49
4.37
4.50
4.50
4.48
4.35
4.59
4.48
7g
7h
7i

4634
X.-L. Wang et al. / European Journal of Medicinal Chemistry 45 (2010) 4631e4639
triazoles 7aei appeared small downfield shifts at 51.6e52.9 ppm in
comparison with that in alkyl-substituted 1,2,3-triazoles 6aef at
50.7e51.0 ppm as a result of the strong electron-withdrawing
character of halogen-substituted aryl moieties in compounds 7aei.
Moreover, the introduction of 1,2,3-triazole ring also results in large
downfield 13C shifts for the methylene carbon of SO2NHCH2 moiety
value of 64
possessed the most potent biological activities against all tested
strains with MIC values between 32 and 64 g/mL. However, the
mg/mL. Notably, compound 6e with dodecyl group
m
antibacterial results showed no obvious inhibition for compounds
6a and 6b with short C5eC6 alkyl chains. Furthermore, 4-amino-N-
((1-hexadecyl-1H-1,2,3-triazol-4-yl)methyl) benzenesulfonamide
6f displayed reduction in inhibitory activity against the tested
stains, compared to compound 6e with C12 alkyl chain. Therefore,
the introduction of alkyl chain with different lengths into sulfa-
nilamide-derived 1,2,3-triazoles has remarkable effect on antibac-
terial activities, and it was unfavorable in enhancing activity to the
incorporation of alkyl chain with lengths too short or too long.
From the bioactive data, it was found that the antibacterial
activities of halobenzyl-substituted sulfanilamide-derived 1,2,3-
triazoles 7aei were generally better than that of alkyl-substituted
compounds 6aef. Among these halobenzyl-substituted series,
compounds 7gei containing 2,4-dichlorobenzyl, 4-flurorobenzyl
and 2,4-diflurorobenzyl groups respectively, displayed moderate
activities against some tested strains at the concentration of
in either alkyl-substituted 1,2,3-triazoles 6aef (
d 39.4e41.5 ppm)
or aryl ones 7aei 37.9e38.4 ppm), compared with their
(d
precursor propargyl sulfonamide 5 (d 31.6 ppm), as seen in Table 1.
2.3. Biological activity
These sulfanilamide-derived 1,2,3-triazoles 6aef and 7aei
containing alkyl and halobenzyl groups were evaluated for their in
vitro antimicrobial activities against the representative bacterial
strains including S. aureus (ATCC25923), methicillin-resistant S.
aureus (MRSA) (N315), and Bacillus subtilis (ATCC6633), Ealmonella
typhosa, Pseudomonas aeruginosa, Shigella dysenteriae, and Escher-
ichia coli (JM109), as well as two fungal strains such as Candida
albicans (ATCC76615) and Candida mycoderma using the two-fold
serial dilution technique [25]. The minimal inhibitory concentra-
16e128 mg/mL, superior to that of chlorobenzyl substituted 1,2,3-
triazoles. Noticeably, compounds 7g and 7i with dichlorobenzyl
and 2,4-diflurorobenzyl moieties respectively, exhibited good
antibacterial activities against all tested strains with MIC values
tion (MIC,
mg/mL) was determined, taking Chloramphenicol and
Fluconazole as the reference drugs. The bioactive data were
summarized in Table 2.
ranging from 16 to 128
mg/mL except for MRSA. Particularly,
sulfanilamide-derived 1,2,3-triazole 7i containing 2,4-difluror-
obenzyl moiety showed excellent antibacterial activities against S.
dysenteriae and P. aeruginosa in comparison with the reference drug
2.3.1. Antibacterial activity
The results of antimicrobial activities indicated that some of the
title compounds showed moderate activities against certain tested
stains in vitro. As seen in Table 2, alkyl-substituted sulfanilamide-
derived 1,2,3-triazoles 6def exhibited comparable antibacterial
activities against P. aeruginosa with MIC values ranging from 32 to
Chloramphenicol with an MIC value of 16 mg/mL. This result was
probably ascribed to the high electro-negativity of fluorine moiety,
which could modify the electronic distribution in the molecule, and
thereby influence the absorption, distribution and metabolism of
the bioactive molecules [21]. These findings indicated that the type
of substitution in the benzene ring has significant influence on
antibacterial activities.
In addition, it was specially noteworthy that propargyl sulfon-
amide 5 as the precurosor of the target compounds, was no
inhibitory activity against all tested strains, while the incorporation
of 1,2,3-triazole dramatically enhanced the antibacterial activities
64
mg/mL, with corresponding reference drug Chloramphenicol.
Meanwhile, it was also observed that these alkyl-substituted
compounds displayed good antibacterial activities against E.
typhosa and S. dysenteriae with MIC values ranging from 32 to
128 mg/mL. Additionally, compound 6d bearing decyl moiety
showed moderate antibacterial activities against B. subtilis
compared with the reference drug Chloramphenicol with an MIC
Table 2
In vitro antibacterial and antifungal activities of compounds 5, 6aef and 7aei.a, b, c
Minimum inhibitory concentration (MIC,
Fungal strains
mg/mL)
Bacterial strains
Compds.
C. albicans
C. mycoderma
S. aureus
B. subtilis
P. aeruginosa
E. coli
S. dysenteriae
MRSA
E. typhosa
5
>512
>512
>512
>512
>512
512
>512
>512
>512
>512
>512
>512
>512
512
>512
>512
>512
512
>512
256
>512
>512
>512
>512
>512
>512
>512
512
>512
>512
512
>512
256
128
256
512
>512
>512
>512
512
512
64
>512
>512
256
256
64
128
256
>512
512
256
>512
>512
>512
128
>512
128
2
>512
512
256
128
64
>512
>512
>512
512
512
64
>512
512
256
256
128
32
128
512
>512
>512
512
>512
>512
32
>512
>512
512
512
512
128
512
256
>512
256
>512
256
>512
128
>512
128
2
>512
512
>512
256
128
64
128
512
512
>512
>512
256
512
128
256
128
2
6a
6b
6c
6d
6e
6f
7a
7b
7c
7d
7e
7f
7g
7h
7i
32
64
256
512
>512
>512
512
512
>512
64
128
16
8
>512
>512
>512
>512
>512
>512
128
256
128
4
>512
256
>512
512
128
64
4
128
16
4
A
e
e
B
0.5
4
e
e
e
e
e
e
e
a
Minimum inhibitory concentrations were determined by two-fold serial dilution method for microdilution plates.
A, chloramphenicol; B, fluconazole.
C. albicans, Candida albicans (ATCC76615); C. mycoderma, Candida mycoderma; S. aureus, Staphylococcus aureus (ATCC25923); B. subtilis, Bacillus subtilis (ATCC6633); P.
b
c
aeruginosa, Pseudomonas aeruginosa; E. coli, Escherichia coli (JM109); S. dysenteriae, Shigella dysenteriae; MRSA, Methicillin-Resistant Staphylococcus aureus (N315); E. typhosa,
Eberthella typhosa.

X.-L. Wang et al. / European Journal of Medicinal Chemistry 45 (2010) 4631e4639
4635
of the sulfonamide. This results manifested that 1,2,3-triazole and
its derivatives are of biological significance, which were expected to
become a new member of antimicrobial agents.
constants (J) are expressed in hertz (Hz) and signals were described
as singlet (s), doublet (d), triplet (t), quartet (q), broad (br) as well as
multiplet (m). The mass spectra were recorded on FINNIGAN TRACE
GC/MS (Thermo Electron Corporation, Bremen, Germany).
Elemental analyses were carried out on a ERBA1106 (Carlo Erba,
Milan, Italy). All chemicals and solvents were commercially avail-
able, and were used without further purification.
In a word, the halobenzyl-substituted sulfanilamide-derived
1,2,3-triazoles 7gei bearing 2,4-dichlorobenzyl, 4-flurorobenzyl
and 2,4-diflurorobenzyl groups respectively, as well as the alkyl-
substituted compounds 6def with decyl, dodecyl and hexadecyl
moieties respectively, showed more potent antibacterial activities
than other new compounds against some tested bacteria species,
while the halobenzyl-substituted compounds exhibited enhanced
activity in contrast to the alkyl-substituted sulfanilamide-derived
1,2,3-triazoles. More importantly, the incorporation of 1,2,3-tri-
azole is beneficial to improve the inhibition activity of the sulfon-
amide precurosor in vitro. All the results suggested the significant
effect of the introduction of 1,2,3-triazole into the sulfanilamide,
the substitution of benzyl group as well as the lengths of linear alkyl
chain in the 1,2,3-triazole ring on antibacterial activities.
4.2. Synthesis of alkyl or benzyl azides
To a stirred solution of alkyl or benzyl bromides (0.5 mmol) in
acetone (20 mL) was added equal equimolar of NaN3 at room
temperature, then the water (10 mL) was added into the solution.
The reaction mixture was refluxed overnight at 60 ꢀC for 10e14 h
(monitored by TLC, eluent, petroleum ether). After cooling to the
room temperature, the solution was evaporated in vacuo and then
water (30 mL) was added. Subsequently, the mixture was extracted
with chloroform (3 ꢂ 30 mL), and all organic phases were
combined, dried over anhydrous Na2SO4 and then evaporated
under reduced pressure to produce liquid azides [26]. The azides
were used in the following reaction without further purification.
2.3.2. Antifungal activity
Unfortunately, the antifungal evaluation revealed that almost all
the synthesized alkyl-substituted and halobenzyl-substituted
sulfanilamide-derived 1,2,3-triazoles exhibited poor antifungal
activities against C. albicans and C. mycoderm, which were relatively
weak in comparison with their antibacterial activities. These results
also validated the fact that sulfanilamide derivatives have no
obvious antifungal activity in vitro, although 1,2,3-triazole ring was
incorporated into the sulfanilamide scaffold.
4.3. Synthesis of 4-(N-acetylamino)benzenesulfonamide (3)
To a stirred solution of acetaniline (5.0 g, 37 mmol) in acetone
(25 mL) was added chlorosulfonic acid (13 mL, 195 mmol) at 0 ꢀC.
The reaction mixture was heated to 60 ꢀC, stirred for 1 h, then
cooled to room temperature and poured into crushed ice. A white
solid was formed, which was isolated by filtration, then dissolved in
acetone (40 mL). At 0 ꢀC, ammonium hydroxide (10 mL) was added.
The mixture was stirred at room temperature for 1 h, and then the
solvent was removed in vacuo to give the intermediate 3 as white
solid in 81% yield which was used in the following reaction without
further purification, mp 217e219 ꢀC in agreement with the
commercial material (mp 219e220 ꢀC).
3. Conclusion
In conclusion, a series of novel sulfanilamide-derived 1,2,3-tri-
azoles with different lengths of alkyl chains and halobenzyl groups
were synthesized successfully via cyclization of azides and terminal
alkyne by ‘click chemistry’. All these new compounds were
confirmed by MS, IR and NMR spectra as well as elemental analyses.
Their antimicrobial activities were evaluated against S. aureus,
MRSA, E. typhosa, P. aeruginosa, S. dysenteriae, B. subtilis, E. coli, as
well as C. albicans and C. mycoderma using the two-fold serial
dilution technique. The results showed that most of the synthesized
sulfanilamide derivatives exhibited moderate antimicrobial activi-
ties in vitro. Especially, compounds 6e, 7g and 7i bearing dodecyl,
2,4-dichlorobenzyl and 2,4-difurobenzyl group, respectively,
showed the most potent antibacterial activities against all tested
4.4. Synthesis of the intermediate (4)
To a stirred mixture of compound 3 (2.0 g, 8 mmol) in acetone
(10 mL) in the presence of potassium carbonate (1.6 g, 11.6 mmol)
was added 3-bromoprop-1-yne (1.8 mL, 23 mmol) at room
temperature. After one hour, tetrabutyl ammonium iodide (TBAI)
(5.0 mg) was added, and then the resulting mixture was stirred
under 45e50 ꢀC for 10e12 h (monitored by TLC, eluent, chloro-
form/ethyl acetate). The solvent was evaporated and then water
(30 mL) was added. Subsequently, the mixture was extracted with
chloroform (3 ꢂ 30 mL), dried over anhydrous Na2SO4 and then
evaporated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (eluent, chloroform/
ethyl acetate) to give the terminal propargyl intermediate 4 as
yellow solid in 65.2% yield, mp 126e128 ꢀC; 1H NMR (300 MHz,
bacterial strains with the MIC values ranging from 32 to 128
mg/mL.
The lengths of the alkyl chain and substitution in the benzyl moiety
played important roles in the antimicrobial activities of the title
compounds. More importantly, the incorporation of 1,2,3-triazole is
helpful to improve the inhibition activity of the sulfonamide
precurosor in vitro. These findings demonstrated that sulfanil-
amide-derived 1,2,3-triazoles are of biological significance, which
have the perspective to become a new member of antimicrobial
agents.
CDCl3):
3, 5-H), 7.51 (s, 1H, CH3CONH), 4.17 (s, 2H, SO2NHCH2), 2.20 (s, 3H,
CH3), 2.07 (s, 1H, ^CH) ppm; 13C NMR (100 MHZ, CDCl3):
167.2
d
7.78 (d, 2H, J ¼ 8.6 Hz, Ar 2, 6-H), 7.67 (d, 2H, J ¼ 8.6 Hz, Ar
4. Experimental
d
(C]O), 143.6 (Ph 4-C), 133.8 (Ph 1-C), 127.9 (Ph 2, 6-C), 113.6 (Ph 3,
5-C), 80.6 (C^CH), 72.4 (^CH), 32.4 (SO2NHCH2), 24.1 (CH3) ppm;
MS (m/z): 275 [M þ Na]þ, 253 [M þ H]þ; Anal. Calcd. for
C11H12N2O3S: C, 52.37; H, 4.79; N, 11.10. Found: C, 52.35; H, 4.78; N,
11.11.
4.1. Chemistry
Melting points were uncorrected and were recorded on X-6
melting point apparatus. TLC analysis was done using pre-coated
silica gel plates. FT-IR spectra were carried out on Bruker RFS100/S
spectrophotometer (Bio-Rad, Cambridge, MA, USA) using KBr
pellets in the 400e4000 cmꢁ1 range. 1H NMR and 13C NMR spectra
were recorded on a Bruker AV 300 pectrometer or Varian-Mercury
400 spectrometer using TMS as an internal standard. The chemical
shifts were reported in parts per million (ppm), the coupling
4.5. Synthesis of 4-amino-N-(prop-2-ynyl)benzenesulfonamide (5)
Concentratedhydrochloric acid(10 mL)wasadded understirring
to a solution of propargyl intermediate 4 in ethanol (20 mL) at room
temperature. The mixture was refluxed for 30 min (monitored by

4636
X.-L. Wang et al. / European Journal of Medicinal Chemistry 45 (2010) 4631e4639
TLC, eluent, chloroform). After cooling to the room temperature, the
pH of the solution was adjusted to the alkaline with sodium
hydroxide, then the solvent was removed in vacuo to give the
deprotected propargyl sulfonamide 5 as light yellow solid in 92%
4.6.3. 4-Amino-N-((1-octyl-1H-1,2,3-triazol-4-yl)methyl)
benzenesulfonamide (6c)
Compound 6c (151 mg) was obtained as yellow solid in 86.8%
yield, mp 129e131 ꢀC; IR (KBr):
n
3353, 3308, 3271 (NH), 3151,
2954, 2855, 2924, 1605, 1526, 1467, 1321, 1146, 1096 cmꢁ1; 1H NMR
(300 MHz, CDCl3):
yield, mp 131e132 ꢀC; IR (KBr):
n
3404, 3339, 3275 (NH), 3250
(^CH), 2925, 2117, 1601, 1523, 1441, 1150, 1097 cmꢁ1; 1H NMR (300
MHz, CDCl3):
d
7.83 (d, 2H, J ¼ 7.7 Hz, Ar 2,6-H), 7.56 (s, 1H,
d
7.83 (d, 2H, J ¼ 8.6 Hz, Ar 2, 6-H), 6.77 (d, 2H,
triazole H), 6.78 (d, 2H, J ¼ 7.8 Hz, Ar 3,5-H), 4.84 (s, 2H, NH2), 4.61
(s, 2H, SO2NHCH2), 4.45 (s, 2H, triazole-CH2), 2.00 (s, 2H, triazole-
J ¼ 8.6 Hz, Ar 3, 5-H), 4.70 (s, 2H, NH2), 4.49 (s, 1H, NH), 4.06 (d, 2H,
J ¼ 3.4 Hz, SO2NHCH2), 2.33 (s, 1H, ^CH) ppm; 13C NMR (100 MHZ,
CH2CH2), 1.41e1.37 (m, 10H, (CH2)5CH3), 0.99 (s, 3H, CH3) ppm; 13
C
CDCl3):
d
151.2 (Ph 4-C), 131.2 (Ph 1-C), 128.6 (Ph 2, 6-C), 112.6 (Ph 3,
NMR (100 MHZ, CDCl3): d 151.8 (Ph 4-C), 145.5 (triazole 4-C), 130.0
5-C), 80.2 (C^CH), 71.6 (^CH), 31.6 (SO2NHCH2) ppm; MS (m/z):
233 [M þ Na]þ, 211 [M þ H]þ; Anal. Calcd. for C9H10N2O2S: C, 51.41;
H, 4.79; N, 13.32. Found: C, 51.42; H, 4.50; N, 13.31.
(Ph 1-C),129.1 (Ph 2, 6-C),122.6 (triazole 5-C),112.8 (Ph 3, 5-C), 50.8
(triazole-CH2), 39.4 (SO2NHCH2), 32.4 (CH3CH2CH2), 31.0 (CH2),
29.8 (CH2), 29.7 (triazole-CH2CH2), 27.2 (triazole-CH2CH2CH2), 23.3
(CH2CH3), 14.8 (CH3) ppm; MS (m/z): 388 [M þ Na]þ, 366 [M þ H]þ;
Anal. Calcd. for C17H27N5O2S: C, 55.86; H, 7.45; N, 19.16. Found: C,
55.88; H, 7.43; N, 19.14.
4.6. General procedure for synthesis of sulfanilamide-derived alkyl
1,2,3-triazoles (6aef)
4.6.4. 4-Amino-N-((1-decyl-1H-1,2,3-triazol-4-yl)methyl)
benzenesulfonamide (6d)
To a solution of propargyl sulfonamide 5 (100 mg, 0.48 mmol) in
a t-BuOH/H2O mixture (10 mL, 1/1, V/V) was added sodium ascor-
bate (0.20 equiv) and copper (II) sulfate pentahydrate (0.10 equiv)
successively. Hereafter excess alkyl azide (0.50 mmol) was added,
and the mixture was stirred for 30e60 min at 60 ꢀC (monitored by
TLC, eluent, chloroform/ethyl acetate). The reaction system was
cooled to room temperature, and the solvent was evaporated under
reduced pressure. Subsequently, the resulting mixture was poured
into water (30 mL) and extracted with ethyl acetate (3 ꢂ 30 mL).
After that, the combined organic layers were dried over anhydrous
Na2SO4 and concentrated under reduced pressure to give the crude
product, which was purified by silica gel column chromatography
(eluent, chloroform/ethyl acetate) to afford the desired cyclization
products 6aef.
Compound 6d (130 mg) was obtained as yellow solid in 69.6%
yield, mp 145e147 ꢀC; IR (KBr):
n
3351, 3308, 3269 (NH), 3162,
2954, 2852, 2922, 1607, 1526, 1466, 1321, 1145, 1096 cmꢁ1; 1H NMR
(300 MHz, CDCl3):
d
7.72 (d, 2H, J ¼ 8.3 Hz, Ar 2,6-H), 7.44 (s, 1H,
triazole H), 6.68 (d, 2H, J ¼ 8.2 Hz, Ar 3,5-H), 4.71 (bs, 2H, NH2), 4.52
(s, 2H, SO2NHCH2), 4.35 (s, 2H, triazole-CH2), 1.89 (s, 2H, triazole-
CH2CH2), 1.32e1.27 (m, 14H, (CH2)7CH3), 0.87 (s, 3H, CH3) ppm; 13
C
NMR (100 MHZ, CDCl3):
d 151.4 (Ph 4-C), 144.5 (triazole 4-C), 133.0
(Ph 1-C), 128.7 (Ph 2, 6-C), 121.1 (triazole 5-C), 112.2 (Ph 3, 5-C), 50.7
(triazole-CH2), 41.4 (SO2NHCH2), 32.0 (CH3CH2CH2), 29.7 (CH2),
29.6 (CH2), 29.5 (CH2), 29.4 (CH2), 29.1 (triazole-CH2CH2), 26.6
(triazole-CH2CH2CH2), 22.8 (CH2CH3), 14.2 (CH3) ppm; MS (m/z):
416 [M þ Na]þ, 394 [M þ H]þ; Anal. Calcd. for C19H31N5O2S: C,
57.99; H, 7.94; N, 17.80. Found: C, 58.02; H, 7.92; N, 17.76.
4.6.1. 4-Amino-N-((1-pentyl-1H-1,2,3-triazol-4-yl)methyl)
benzenesulfonamide (6a)
4.6.5. 4-Amino-N-((1-dodecyl-1H-1,2,3-triazol-4-yl)methyl)
benzenesulfonamide (6e)
Compound 6a (121 mg) was obtained as yellow solid in 78.6%
yield, mp 148e150 ꢀC; IR (KBr):
n
3353, 3308, 3275 (NH), 3160,
2955, 2862, 2932, 1604, 1526, 1467, 1321, 1146, 1097 cmꢁ1; 1H NMR
(300 MHz, CDCl3):
Compound 6e (166 mg) was obtained as yellow solid in 82.6%
yield, mp 141e143 ꢀC; IR (KBr):
n
3352, 3310, 3269 (NH), 3161, 2954,
2851, 2921, 1606, 1526, 1467, 1321, 1146, 1097 cmꢁ1 1H NMR
(300 MHz, CDCl3):
d
7.83 (d, 2H, J ¼ 7.6 Hz, Ar 2,6-H), 7.56 (s, 1H,
;
triazole H), 6.78 (d, 2H, J ¼ 7.3 Hz, Ar 3,5-H), 4.94 (bs, 1H, NH), 4.61
(s, 2H, SO2NHCH2), 4.44 (s, 2H, triazole-CH2), 2.38 (s, 2H, triazole-
CH2CH2), 1.43 (s, 4H, (CH2)2CH3), 1.00 (s, 3H, CH3) ppm; 13C NMR
d
7.72 (d, 2H, J ¼ 8.6 Hz, Ar 2,6-H), 7.44 (s, 1H,
triazole H), 6.67 (d, 2H, J ¼ 8.6 Hz, Ar 3,5-H), 4.86 (bs, 1H, NH), 4.71
(bs, 2H, NH2), 4.50 (d, 2H, J ¼ 5.1 Hz, SO2NHCH2), 4.31 (t, 2H,
J ¼ 7.3 Hz, triazole-CH2), 1.89 (t, 2H, J ¼ 6.4 Hz, triazole-CH2CH2),
(100 MHZ, CDCl3): d 151.2 (Ph 4-C), 145.3 (triazole 4-C), 130.8 (Ph 1-
C), 129.0 (Ph 2, 6-C), 122.8 (triazole 5-C), 112.6 (Ph 3, 5-C), 51.0
(triazole-CH2), 39.5 (SO2NHCH2), 29.5 (CH3CH2CH2), 28.2 (triazole-
CH2CH2), 22.6 (CH2CH3), 14.2 (CH3) ppm; MS (m/z): 346 [M þ Na]þ,
324 [M þ H]þ; Anal. Calcd. for C14H21N5O2S: C, 51.99; H, 6.54; N,
21.65. Found: C, 51.96; H, 6.56; N, 21.62.
1.31e1.25 (m, 18H, (CH2)9CH3), 0.88 (t, 3H, J ¼ 6.4 Hz, CH3) ppm; 13
C
NMR (100 MHz, CDCl3):
d 151.4 (Ph 4-C), 144.2 (triazole 4-C), 133.6
(Ph 1-C), 128.4 (Ph 2, 6-C), 121.6 (triazole 5-C), 111.8 (Ph 3, 5-C), 50.7
(triazole-CH2), 41.0 (SO2NHCH2), 32.4 (CH3CH2CH2), 29.8 (CH2),
29.7 (CH2), 29.5 (CH2), 29.2 (CH2), 29.0 (CH2), 28.9 (CH2), 28.1
(triazole-CH2CH2), 26.1 (triazole-CH2CH2CH2), 21.8 (CH2CH3), 14.6
(CH3) ppm; MS (m/z): 444 [M þ Na]þ, 422 [M þ H]þ; Anal. Calcd. for
C21H35N5O2S: C, 59.83; H, 8.37; N, 16.61. Found: C, 59.79; H, 8.35; N,
16.64.
4.6.2. 4-Amino-N-((1-hexyl-1H-1,2,3-triazol-4-yl)methyl)
benzenesulfonamide (6b)
Compound 6b (143 mg) was obtained as white solid in 88.8%
yield, mp 138e140 ꢀC; IR (KBr):
n
3352, 3311, 3269 (NH), 3157,
2956, 2850, 2919, 1606, 1526, 1468, 1321, 1146, 1056 cmꢁ1; 1H NMR
(300 MHz, CDCl3):
4.6.6. 4-Amino-N-((1-hexadecyl-1H-1,2,3-triazol-4-yl)methyl)
benzenesulfonamide (6f)
d
7.71 (d, 2H, J ¼ 8.2 Hz, Ar 2,6-H), 7.44 (s, 1H,
triazole H), 6.66 (d, 2H, J ¼ 8.3 Hz, Ar 3,5-H), 4.70 (bs, 2H, NH2),
4.50 (s, 2H, SO2NHCH2), 4.33 (t, 2H, J ¼ 7.1 Hz, triazole-CH2), 1.89 (s,
2H, triazole-CH2CH2), 1.31e1.25 (m, 6H, (CH2)3CH3), 0.88 (s, 3H,
Compound 6f (160 mg) was obtained as white solid in 70.2%
yield, mp 144e145 ꢀC; IR (KBr):
n
3353, 3311, 3269 (NH), 3157, 2954,
2850, 2919, 1606, 1526, 1468, 1321, 1146, 1097 cmꢁ1 1H NMR
(300 MHz, CDCl3):
;
CH3) ppm; 13C NMR (100 MHZ, CDCl3):
d
151.5 (Ph 4-C), 145.8
d
7.72 (d, 2H, J ¼ 8.3 Hz, Ar 2, 6-H), 7.44 (s, 1H,
(triazole 4-C), 131.2 (Ph 1-C), 128.5 (Ph 2, 6-C), 122.3 (triazole 5-C),
112.3 (Ph 3, 5-C), 50.8 (triazole-CH2), 39.6 (SO2NHCH2), 31.6
(CH3CH2CH2), 30.7 (triazole-CH2CH2), 26.6 (triazole-CH2CH2CH2),
22.9 (CH2CH3), 14.5 (CH3) ppm; MS (m/z): 360 [M þ Na]þ; Anal.
Calcd. for C15H23N5O2S: C, 53.39; H, 6.87; N, 20.75. Found: C, 53.35;
H, 6.90; N, 20.72.
triazole H), 6.66 (d, 2H, J ¼ 8.3 Hz, Ar 3,5-H), 4.84 (bs, 1H, NH), 4.65
(s, 2H, SO2NHCH2), 4.50 (s, 2H, triazole-CH2), 4.33 (s, 2H, NH2), 1.89
(s, 2H, triazole-CH2CH2), 1.30e1.25 (m, 26H, (CH2)13CH3), 0.88 (t,
3H, J ¼ 6.3 Hz, CH3) ppm; 13C NMR (100 MHz, CDCl3):
d 151.6 (Ph 4-
C), 144.8 (triazole 4-C), 133.2 (Ph 1-C), 127.9 (Ph 2, 6-C), 121.4 (tri-
azole 5-C), 112.3 (Ph 3, 5-C), 50.8 (triazole-CH2), 41.5 (SO2NHCH2),

X.-L. Wang et al. / European Journal of Medicinal Chemistry 45 (2010) 4631e4639
4637
31.8 (CH3CH2CH2), 29.8 (CH2), 29.1 (CH2), 28.6 (CH2), 28.5 (triazole-
CH2CH2), 27.5 (triazole-CH2CH2CH2), 22.9 (CH2CH3), 14.5 (CH3)
ppm; MS (m/z): 500 [M þ Na]þ, 478 [M þ H]þ; Anal. Calcd. for
C25H43N5O2S: C, 62.86; H, 9.07; N,14.66. Found: C, 62.87; H, 9.05; N,
14.64.
DMSO-d6): d 150.7 (p-NH2Ph 4-C), 147.2 (p-NO2Ph 4-C), 145.2
(triazole 4-C), 143.3 (p-NO2Ph 1-C), 128.8 (p-NO2Ph 2, 6-C), 128.6
(p-NH2Ph 1-C), 128.3 (p-NH2Ph 2, 6-C), 127.2 (triazole 5-C), 123.7
(p-NO2Ph 3, 5-C) 111.1 (p-NH2Ph 3, 5-C), 51.8 (triazole-CH2), 37.9
(SO2NHCH2) ppm; MS (m/z): 412 [M þ Na]þ; Anal. Calcd. for
C16H16N6O4S: C, 49.48; H, 4.15; N, 21.64. Found: C, 49.49; H, 4.13; N,
21.63.
4.7. General procedure for synthesis of sulfanilamide-derived aryl
1,2,3-triazoles (7aei)
4.7.4. 4-Amino-N-((1-(2-chlorobenzyl)-1H-1,2,3-triazol-4-yl)
methyl)benzenesulfonamide (7d)
To a solution of propargyl sulfonamide 5 (100 mg, 0.48 mmol) in
a t-BuOH/H2O mixture (10 mL, 1/1, V/V) were added sodium
ascorbate (0.2 equiv) and copper (II) sulfate pentahydrate
(0.1 equiv) successively. Hereafter excess aryl azide (0.50 mmol)
was added, and the mixture was stirred at 60 ꢀC. After 25e45 min,
the reaction came to the end (monitored by TLC, eluent, chloro-
form/ethyl acetate), and then solvent was evaporated under
reduced pressure. Subsequently, the resulting mixture was poured
into water (30 mL) and extracted with ethyl acetate (3 ꢂ 30 mL).
After that, the combined organic layers were dried over anhydrous
Na2SO4 and concentrated under reduced pressure to give the crude
material, which was purified by silica gel column chromatography
(eluent, chloroform/ethyl acetate) to afford the desired cyclization
products 7aei.
Compound 7d (123 mg) was obtained as white solid in 68.6%
yield, mp 176e178 ꢀC; IR (KBr):
n
3379, 3269 (NH), 3153, 2868,
1604,1520,1475, 1312,1149, 1098 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
7.73 (d, 2H, J ¼ 8.7 Hz, Ar H), 7.44 (s, 1H, triazole H), 7.10e7.07 (m,
4H, Ar H), 6.67 (d, 2H, J ¼ 8.7 Hz, Ar H), 5.67 (s, 2H, triazole-CH2),
4.62 (bs, 2H, NH2), 4.50 (s, 2H, SO2NHCH2) ppm; 13C NMR (100 MHZ,
DMSO-d6):
d 150.8 (p-NH2Ph 4-C), 145.0 (triazole 4-C), 133.2 (o-
ClPh 1-C), 132.4 (o-ClPh 2-C), 130.5 (o-ClPh 6-C), 130.2 (p-NH2Ph 1-
C), 130.0 (o-ClPh 3-C), 129.5 (p-NH2Ph 2, 6-C), 127.6 (o-ClPh 4-C),
127.1 (o-ClPh 5-C), 123.3 (triazole 5-C), 111.1 (p-NH2Ph 3, 5-C), 51.6
(triazole-CH2), 37.9 (SO2NHCH2) ppm; MS (m/z): 400 [M þ Na]þ,
378 [M þ H]þ; Anal. Calcd. for C16H16ClN5O2S: C, 50.86; H, 4.27; N,
18.53. Found: C, 50.88; H, 4.26; N, 18.51.
4.7.1. 4-Amino-N-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)
benzenesulfonamide (7a)
4.7.5. 4-Amino-N-((1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl)
methyl)benzenesulfonamide (7e)
Compound 7a (147 mg) was obtained as yellow solid in 90.2%
Compound 7e (141 mg) was obtained as white solid in 78.3%
yield, mp 136e137 ꢀC; IR (KBr):
n
3360, 3269 (NH), 3149, 3060,
2865, 1601, 1519, 1455, 1312, 1148, 1097 cmꢁ1 1H NMR (300 MHz,
CDCl3):
yield, mp 151e153 ꢀC; IR (KBr):
n
3380, 3332 (NH), 3153, 2865,1603,
;
1520,1472,1313,1149,1098 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
7.72
d
7.66 (d, 2H, J ¼ 8.3 Hz, Ar H), 7.49 (s, 1H, triazole H),
(d, 2H, J ¼ 8.6 Hz, Ar H), 7.61 (s, 1H, triazole H), 7.40e7.15 (m, 4H, Ar
H), 6.65 (d, 2H, J ¼ 8.6 Hz, Ar H), 5.50 (s, 2H, triazole-CH2), 4.62 (s,
2H, NH2), 4.50 (s, 2H, SO2NHCH2) ppm; 13C NMR (100 MHz, DMSO-
7.40e7.27 (m, 4H, Ar H), 6.64 (d, 2H, J ¼ 8.4 Hz, Ar H), 5.94 (s, H, NH),
5.51 (s, 2H, triazole-CH2), 4.45 (d, 2H, J ¼ 5.5 Hz, SO2NHCH2) ppm;
13C NMR (100 MHz, DMSO-d6):
d
150.9 (p-NH2Ph 4-C), 145.2 (tri-
d6): d 150.8 (p-NH2Ph 4-C), 145.2 (triazole 4-C), 138.4 (m-ClPh 1-C),
azole 4-C), 136.1 (CH2Ph 1-C), 130.5 (p-NH2Ph 1-C), 128.6 (CH2Ph 2,
6-C), 128.0 (CH2Ph 3, 5-C), 127.8 (p-NH2Ph 2, 6-C), 127.2 (CH2Ph 4-
C), 122.9 (triazole 5-C), 111.1 (p-NH2Ph 3, 5-C), 52.7 (triazole-CH2),
37.9 (SO2NHCH2) ppm; MS (m/z): 366 [M þ Na]þ; Anal. Calcd. for
C16H17N5O2S: C, 55.96; H, 4.99; N, 20.39. Found: C, 55.98; H, 4.97; N,
20.38.
133.1 (m-ClPh 3-C), 130.5 (m-ClPh 5-C), 127.9 (p-NH2Ph 1-C), 127.6
(m-ClPh 2-C), 127.1 (p-NH2Ph 2, 6-C), 126.5 (m-ClPh 6-C), 123.0
(triazole 5-C), 111.0 (p-NH2Ph 3, 5-C), 51.8 (triazole-CH2), 37.9
(SO2NHCH2) ppm; MS (m/z): 400 [M þ Na]þ, 378 [M þ H]þ; Anal.
Calcd. for C16H16ClN5O2S: C, 50.86; H, 4.27; N, 18.53. Found: C,
50.88; H, 4.26; N, 18.51.
4.7.2. 4-Amino-N-((1-(3-methyl)-1H-1,2,3-triazol-4-yl)methyl)
benzenesulfonamide (7b)
4.7.6. 4-Amino-N-((1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl)
methyl)benzenesulfonamide (7f)
Compound 7b (133 mg) was obtained as white solid in 78.3%
Compound 7f (124 mg) was obtained as yellow solid in 68.9%
yield, mp 195e197 ꢀC; IR (KBr):
n
3390, 3296 (NH), 3148, 3067,
2943, 2859, 2915, 1595, 1517, 1460, 1313, 1142, 1034 cmꢁ1; 1H NMR
(300 MHz, CDCl3):
yield, mp 152e153 ꢀC; IR (KBr):
n
3381, 3334 (NH), 3151, 2864,1603,
1520, 1471, 1315, 1150, 1010 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
7.71
d
7.71 (d, 2H, J ¼ 8.4 Hz, Ar H), 7.38 (s, 1H, triazole
(d, 2H, J ¼ 8.6 Hz, Ar H), 7.47 (s, 1H, triazole H), 7.18e7.26 (m, 4H, Ar
H), 6.64 (d, 2H, J ¼ 8.6 Hz, Ar H), 5.49 (s, 2H, triazole-CH2), 4.63 (bs,
1H, NH), 4.48 (s, 2H, SO2NHCH2) ppm; 13C NMR (100 MHz, DMSO-
H), 7.19e7.07 (m, 3H, Ar H), 6.65 (d, 2H, J ¼ 8.3 Hz, Ar H), 5.48 (s, 2H,
triazole-CH2), 4.61 (s, 2H, NH2), 4.49 (s, 2H, SO2NHCH2), 2.34 (s, 3H,
CH3) ppm; 13C NMR (100 MHz, DMSO-d6):
d
151.1 (p-NH2Ph 4-C),
d6): d 150.8 (p-NH2Ph 4-C), 145.2 (triazole 4-C), 135.0 (p-ClPh 1-C),
145.3 (triazole 4-C), 138.1 (m-CH3Ph 3-C), 136.1 (m-CH3Ph 1-C),
130.7 (m-CH3Ph 2-C), 128.8 (p-NH2Ph 1-C), 128.8 (m-CH3Ph 5-C),
128.6 (p-NH2Ph 2, 6-C), 127.4 (m-CH3Ph 4-C), 125.1 (m-CH3Ph 6-C),
123.1 (triazole 5-C), 111.3 (p-NH2Ph 3, 5-C), 52.9 (triazole-CH2), 38.1
(SO2NHCH2), 21.0 (CH3) ppm; MS (m/z): 380 [M þ Na]þ; Anal. Calcd.
for C17H19N5O2S: C, 57.12; H, 5.36; N, 19.59. Found: C, 57.13; H, 5.34;
N, 19.57.
132.7 (p-ClPh 4-C), 130.5 (p-ClPh 2, 6-C), 129.7 (p-NH2Ph 1-C), 128.6
(p-ClPh 3, 5-C), 127.1 (p-NH2Ph 2, 6-C), 122.9 (triazole 5-C), 111.0 (p-
NH2Ph 3, 5-C), 51.8 (triazole-CH2), 38.4 (SO2NHCH2) ppm; MS (m/
z): 400 [M þ Na]þ; Anal. Calcd. for C16H16ClN5O2S: C, 50.86; H, 4.27;
N, 18.53. Found: C, 50.88; H, 4.26; N, 18.51.
4.7.7. N-((1-(2,4-dichlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-4-
aminobenzenesulfonamide (7g)
4.7.3. N-((1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-4-
aminobenzenesulfonamide (7c)
Compound 7g (177 mg) was obtained as yellow solid in 90.2%
yield, mp 147e149 ꢀC; IR (KBr):
n
3366, 3336 (NH), 3145, 2865,1597,
;
Compound 7c (162 mg) was obtained as yellow solid in 87.5%
1513, 1474, 1334, 1153, 1052 cmꢁ1 1H NMR (300 MHz, DMSO-d6):
yield, mp 167e168 ꢀC; IR (KBr):
n
3383, 3330 (NH), 3151, 2865,1605,
d
7.72 (d, 2H, J ¼ 8.5 Hz, Ar H), 7.43 (s, 1H, triazole H), 6.88 (m, 2H, Ar
1523, 1314, 1149, 1111 cmꢁ1
;
1H NMR (300 MHz, DMSO-d6):
d
8.23
H), 6.64 (d, 2H, J ¼ 8.6 Hz, Ar H), 5.65 (s, 2H, triazole-CH2), 4.73 (bs,
(d, 2H, J ¼ 8.6 Hz, Ar H), 8.11 (s, 1H, triazole H), 7.51 (m, 4H, Ar H),
6.87 (s, H, NH), 6.69 (d, 2H, J ¼ 8.4 Hz, Ar H), 5.76 (s, 2H, triazole-
CH2), 4.37 (d, 2H, J ¼ 5.4 Hz, SO2NHCH2) ppm; 13C NMR (100 MHz,
1H, NH), 4.35 (s, 2H, SO2NHCH2) ppm; 13C NMR (100 MHz, DMSO-
d6):
d 150.5 (p-NH2Ph 4-C), 143.9 (triazole 4-C), 134.3 (2, 4-Cl2Ph
1-C), 133.4 (2, 4-Cl2Ph 2-C), 131.3 (2, 4-Cl2Ph 4-C), 130.9 (2, 4-Cl2Ph

4638
X.-L. Wang et al. / European Journal of Medicinal Chemistry 45 (2010) 4631e4639
6-C), 130.7 (2, 4-Cl2Ph 3-C), 128.9 (p-NH2Ph 1-C), 127.3 (p-NH2Ph 2,
6-C), 127.2 (2, 4-Cl2Ph 5-C), 122.9 (triazole 5-C), 111.1 (p-NH2Ph 3, 5-
C), 51.6 (triazole-CH2), 38.3 (SO2NHCH2) ppm; MS (m/z): 437
[M þ Na]þ; Anal. Calcd. for C16H15Cl2N5O2S: C, 46.61; H, 3.67; N,
16.99. Found: C, 46.63; H, 3.66; N, 16.97.
a control test was performed with test medium supplemented with
DMSO at the same dilutions as used in the experiment.
4.8.2. Antifungal assays
The newly synthesized compounds were evaluated for their
antifungal activity against C. albicans (ATCC76615) and C. myco-
derma. A spore suspension in sterile distilled water was prepared
from 1-day old culture of the fungi growing on Sabouraud agar (SA)
4.7.8. 4-Amino-N-((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)
methyl)benzenesulfonamide (7h)
Compound 7h (118 mg) was obtained as white solid in 68.6%
media. The final spore concentration was 1e5 ꢂ103 spore mLꢁ1
.
yield, mp 162e164 ꢀC; IR (KBr):
n
3381, 3336 (NH), 3152, 2928,
2864, 1605, 1512, 1472, 1315, 1222, 1149, 1010 cmꢁ1 1H NMR
(300 MHz, CDCl3):
From the stock solutions of the tested compounds and reference
antifungal Fluconazole, dilutions in sterile RPMI 1640 medium
(Neuronbc Laboraton Technology CO., Ltd, Beijing, China) were
;
d
7.83 (d, 2H, J ¼ 7.5 Hz, Ar H), 7.48 (s, 1H, triazole
H), 7.20 (m, 2H, Ar H), 6.76 (d, 2H, J ¼ 7.4 Hz, Ar H), 5.61 (s, 2H,
made resulting in eleven desired concentrations (0.5e512 mg/mL)
triazole-CH2), 4.91 (bs, 1H, NH), 4.75 (s, 2H, NH2), 4.59 (s, 2H,
of each tested compound. These dilutions were inoculated and
incubated at 35 ꢀC for 24 h. The drug MIC was defined as the first
well with an approximate 80% reduction in growth compared to the
growth of the drug-free well. The minimum inhibitory concentra-
SO2NHCH2) ppm; 13C NMR (100 MHz, DMSO-d6):
d 163.0, 160.5 (p-
FPh 4-C), 150.9 (p-NH2Ph 4-C), 145.2 (triazole 4-C), 132.3 (p-FPh 1-
C), 130.5 (p-NH2Ph 1-C), 130.2, 130.1 (p-FPh 2, 6-C), 127.2 (p-NH2Ph
2, 6-C), 122.8 (triazole 5-C), 115.6, 115.4 (p-FPh 3, 5-C), 111.1 (p-
NH2Ph 3, 5-C), 51.9 (triazole-CH2), 38.4 (SO2NHCH2) ppm; MS (m/
z): 384 [M þ Na]þ, 362 [M þ H]þ; Anal. Calcd. for C16H16FN5O2S: C,
53.17; H, 4.46; N, 19.38. Found: C, 53.15; H, 4.48; N, 19.36.
tion values (MICs) (in mg/mL) were summarized in Table 2.
Acknowledgments
This work was partially supported by Natural Science Founda-
tion of Chongqing (CSCT: 2007BB5369, 2009BB5296) and South-
west University (SWUB2006018, XSGX0602).
4.7.9. 4-Amino-N-((1-(2,4-difluorobenzyl)-1H-1,2,3-triazol-4-yl)
methyl)benzenesulfonamide (7i)
Compound 7i (160 mg) was obtained as white solid in 88.5%
yield, mp 172e174 ꢀC; IR (KBr):
n
3379, 3335 (NH), 3156, 2866, 1604,
1520,1475,1314,1149,1098 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
7.71
References
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NH), 4.63 (s, 2H, NH2), 4.48 (s, 2H, SO2NHCH2) ppm; 13C NMR
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