Design and synthesis of novel sulfonamide-derived triazoles and bioactivity exploration

Article abstract of DOI:10.2174/1573406414666181106124852

Objective: Due to the incidence of resistance, a series of sulfonamide-derived 1,2,4-triazoles were synthesized and evaluated. Method: The novel sulfonamide-derived 1,2,4-triazoles were prepared starting from commercial acetaniline and chlorosulfonic acid by sulfonylation, aminolysis, N-alkylation and so on. The antimicrobial activity of the synthesized compounds were evaluated in vitro by two-fold serial dilution technique. Results: In vitro antimicrobial evaluation found that 2-chlorobenzyl sulfonamide 1,2,4-triazole 7c exhibited excellent antibacterial activities against MRSA, B. subtilis, B. typhi and E. coli with MIC values of 0.02?0.16 μmol/mL, which were comparable or even better than Chloromycin. The preliminary mechanism suggested that compound 7c could effectively bind with DNA, and also it could bind with human microsomal heme through hydrogen bonds in molecular docking. Computational chemical studies were performed on compound 7c to understand the structural features that are essential for activity. Additionally, compound 7c could generate a small amount of reactive oxygen species (ROS). Conclusion: Compound 7c could serve as a potential clinical antimicrobial candidate.

Full text of DOI:10.2174/1573406414666181106124852

104
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Medicinal Chemistry, 2020, 16, 104-118
RESEARCH ARTICLE
ISSN: 1573-4064
eISSN: 1875-6638
Impact
Factor:
2.53
Design and Synthesis of Novel Sulfonamide-Derived Triazoles and Bio-
activity Exploration
Shi-Chao He1,2, Hui-Zhen Zhang1,*, Hai-Juan Zhang1, Qing Sun1 and Cheng-He Zhou2*
2
1School of Pharmacy, Linyi University, Linyi 276000, P.R. China, School of Chemistry and Chemical Engineering,
Southwest University, Chongqing 400715, P.R. China
Abstract: Objective: Due to the incidence of resistance, a series of sulfonamide-derived 1,2,4-
triazoles were synthesized and evaluated.
Method: The novel sulfonamide-derived 1,2,4-triazoles were prepared starting from commercial
A R T I C L E H I S T O R Y
acetaniline and chlorosulfonic acid by sulfonylation, aminolysis, N-alkylation and so on. The an-
timicrobial activity of the synthesized compounds were evaluated in vitro by two-fold serial dilu-
tion technique.
Received: July 16, 2018
Revised: October 29, 2018
Accepted: October 30, 2018
Results: In vitro antimicrobial evaluation found that 2-chlorobenzyl sulfonamide 1,2,4-triazole 7c
exhibited excellent antibacterial activities against MRSA, B. subtilis, B. typhi and E. coli with MIC
DOI:
10.2174/1573406414666181106124852
values of 0.02−0.16 μmol/mL, which were comparable or even better than Chloromycin. The pre-
liminary mechanism suggested that compound 7c could effectively bind with DNA, and also it
could bind with human microsomal heme through hydrogen bonds in molecular docking. Compu-
tational chemical studies were performed on compound 7c to understand the structural features
that are essential for activity. Additionally, compound 7c could generate a small amount of reac-
tive oxygen species (ROS).
Conclusion: Compound 7c could serve as a potential clinical antimicrobial candidate.
Keywords: Antibacterial, antifungal, antimicrobial agents, cytotoxicity, sulfonamides, triazole.
1. INTRODUCTION
the growth of microorganisms. Up to now, numerous sul-
fonamide derivatives containing aromatic rings have been
successfully marketed and widely employed in the treatment
of infections Fig. (1) [9]. Significantly, supramolecular Ag-
sulfadiazine used in burn therapy exhibited a better therapeu-
tic effect than the free ligand or AgNO3 Fig. (1) [10]. Re-
cently, numerous efforts have been devoted to the further
development of the novel sulfonamide derivatives with high
activity, broad antimicrobial spectrum and low toxicity [11-
14].
In the past few decades, the incidence of systemic micro-
bial infections has rapidly increased and become a major
threat to public health. Various synthetic drugs such as sul-
fonamides, quinolones, azoles and so on are available
throughout the world, however, the overuse of anti-infective
drugs for the prevention and treatment of diseases has accel-
erated the dramatic growing emergence of drug resistance.
Especially, the occurrence of multi-drug resistant bacteria
and fungi has become a severe problem in both community
and hospital-acquired infections. Therefore, the discovery of
novel structurally antimicrobial agents with good pharma-
cological profiles and excellent activity toward resistant
strains is highly desirable [1].
1,2,4-Triazole derivatives are known as an important type
of poly-nitrogen electron-rich heterocyclic compounds with
excellent safety profiles, favorable pharmacokinetic charac-
teristics and the capability of forming hydrogen bonds [15,
16]. Therefore, the introduction of 1,2,4-triazole fragment is
beneficial to improve the binding capacity with biomolecular
targets and increase water solubility of target compounds. So
far, a plenty of predominant triazole-based drugs have been
successfully developed and prevalently used in antimicrobial
field, such as Fluconazole, Itraconazole, Voriconazole, Posa-
conazole, Efinaconazole and Terconazole etc. [17]. Notably,
it is commonly considered that the 1,2,4-triazole ring in Flu-
conazole can efficiently coordinate with the Fe2+ in human
microsomal heme protein to restrain the biosynthesis of er-
Sulfonamides as important artificial antimicrobial agents
have been widely used in the clinic since 80 years ago. Cur-
rently, sulfonamide compounds have attracted increasing
attention due to various biological activities [2] such as an-
timicrobial [3-5], anticancer [6] and so on [7, 8]. As already
reported, sulfonamides could compete with aminobenzoic
acid to affect the synthesis of nucleic acid, and then interrupt
*Address correspondence to this author at the School of Pharmacy, Linyi
University, Linyi 276000, P.R. China; Tel: +86-539-7258637; Fax: +86-
539-7258637; E-mail: zhanghuizhen@lyu.edu.cn
1875-6638/20 $65.00+.00
© 2020 Bentham Science Publishers

Bioactivity Exploration of Sulfonamide-Derived Triazoles
Medicinal Chemistry, 2020, Vol. 16, No. 1 105
O
S
HN
NH2
N
O
O
S
MeO
N
Sulfadimethoxine
HN
NH2
O
OMe
O
HN
S
NH2
N
N
O
Sulfachlorpyridazine
H2N
O
Cl
O
Sulfafurazole
Ag+
N
O
S
O
N
H2N
S
NH2
HN
S
NH2
N
O
O
S
O
N
Silver sulfadiazine
Sulfathiazole
Parent sulfonamide
N
Fig. (1). Structures of sulfonamide-derived clinical drugs.
2. EXPERIMENTAL
2.1. General Methods
gosterol, thus inhibiting the growth of fungi [18]. The above
observations strongly suggest that 1,2,4-triazole derivatives
possess large potentiality as novel antimicrobial agents.
2.1.1. Synthesis of 4-acetamidobenzene-1-sulfonyl Chloride
(2)
Therefore, the exploration of newly structural molecules
with sulfonamide nucleus and 1,2,4-triazole moiety has be-
come one of the predominant directions [19]. Inspired by
these observations, a series of novel sulfonamide-derived
1,2,4-triazoles were designed from the following respects
Fig. (1).
The desired 4-acetamidobenzene-1-sulfonyl chloride 2
was synthesized as white solid [11]. Yield: 90%; mp: 139-
140ºC. (literature mp: 142-144ºC).
2.1.2. Synthesis of N- (4-sulfamoylphenyl) acetamide (3)
(a) As was reported, tertiary amino moiety as the bioisos-
tere of tertiary alcohol fragment could be employed for the
drug design to regulate physicochemical properties of bio-
molecules and interact with various enzymes and receptors
in biological systems to exert bioactivities [20].
The N-(4-sulfamoylphenyl) acetamide 3 was obtained as
white solid [11]. Yield: 82%; mp: 212–214ºC. (literature mp:
219-220ºC).
2.1.3. Synthesis of N-(4-(N-(2-chlorobenzyl) sulfamoyl)
phenyl) acetamide (4a)
(b) Various halobenzyl groups were employed into the
target compounds because numerous works has shown that
the incorporation of halobenzyl moieties was beneficial to
improve biological and pharmacological properties by en-
hancing the rate of absorption and transport of drugs in vivo
[21].
A mixture of compound 3 (5.094 g, 23.8 mmol) and po-
tassium carbonate (2.324 g, 16.8 mmol) was stirred in ace-
tone (60 mL) at 50ºC. 1-Chloro-2- (chloromethyl)benzene
(3.821 g, 23.7 mmol) was added and the reaction system was
stirred at 70ºC continuously after 0.5 h. When the reaction
was completed (monitored by TLC, eluent, chloroform/ethyl
acetate, 5/1, V/V), the system was filtered and washed with
methanol (3 × 25 mL). Compound 4a was obtained and puri-
fied as white solid by silica gel column chromatography
(eluent, chloroform/ethyl acetate, 10/1, V/V). Yield: 17%;
mp: 180–182ºC; IR (KBr) ν: 3301 (N−H), 3107, 3062 (aro-
matic C−H), 2924, 2856 (aliphatic C−H), 1678 (C=O), 1592,
(c) Ethylene chain could modulate the molecular flexibil-
ity, which might be helpful to improve molecular binding
ability with the microbial targets [20].
Based on the above considerations, a series of novel sul-
fonamide-derived 1,2,4-triazoles were synthesized in two
ways. The in vitro antibacterial and antifungal activities were
evaluated against four Gram-positive bacteria, four Gram-
negative bacteria and five fungi. The interaction of the bioac-
tive molecule with calf thymus DNA was performed and
molecular computational studies were employed to investi-
gate the possible antibacterial mechanism. Moreover, the
cytotoxicity, ROS and docking with human microsomal
heme of active compound were also investigated to explore
its further biological activity [22, 23].
1
1530 (aromatic frame), 1333, 1158, 756 cm-1; H NMR (600
MHz, DMSO-d6) δ: 10.31 (s, 1H, NHCOCH3), 8.08 (t, J =
6.1 Hz, 1H, SO2NH), 7.77–7.69 (apparent s, 4H, Ph-H),
7.44–7.42 (m, 1H, 2-ClPh-3-H), 7.38 (d, J = 7.3 Hz, 1H, 2-
ClPh-6-H), 7.32–7.26 (m, 2H, 2-ClPh-4,5-H), 4.03 (d, J =
6.2 Hz, 2H, 2-ClPh-CH2), 2.09 (s, 3H, COCH3) ppm; 13C
NMR (151 MHz, DMSO-d6) δ: 169.4, 143.3, 135.4, 134.6,
132.6, 130.2, 129.5, 129.4, 128.1, 127.6, 119.1, 44.1, 24.6
ppm.

106 Medicinal Chemistry, 2020, Vol. 16, No. 1
He et al.
2.1.4. Synthesis of N-(4-(N-(4-fluorobenzyl) sulfamoyl)
phenyl) acetamide (4b)
C−H), 1679 (C=O), 1592, 1529 (aromatic frame), 1369,
1155, 748 cm-1; 1H NMR (600 MHz, DMSO-d6) δ: 10.29 (s,
1H, NHCOCH3), 8.11 (t, J = 5.7 Hz, 1H, SO2NH), 7.73 (d, J
= 8.9 Hz, 2H, Ph-2, 6-H), 7.70–7.68 (m, 2H, Ph-3,5-H), 7.53
(d, J = 8.3 Hz, 1H, 2,3-Cl2Ph-5-H), 7.43 (d, J = 1.9 Hz, 1H,
2,3-Cl2Ph-2-H), 7.23 (dd, J = 8.3, 2.0 Hz, 1H, 2,3-Cl2Ph-6-
H), 3.99 (d, J = 5.6 Hz, 2H, 2,3-Cl2Ph-CH2), 2.09 (s, 3H,
COCH3) ppm; 13C NMR (151 MHz, DMSO-d6) δ: 169.4,
143.3, 139.6, 134.7, 131.3, 130.8, 130.1, 129.9, 128.3, 128.1,
119.0, 45.3, 24.6 ppm.
Compound 4b was prepared according to the procedure
described for compound 4a starting from compound 3 (3.005
g, 14.0 mmol) and 1-(chloromethyl)-4-fluorobenzene (2.003
g, 13.9 mmol). The pure product 4b was obtained as white
solid. Yield: 7%; mp: 196–198ºC; IR (KBr) ν: 3304 (N−H),
3100, 3048 (aromatic C−H), 2930, 2859 (aliphatic C−H),
1672 (C=O), 1590, 1531 (aromatic frame), 1343, 1163, 748,
1
611 cm-1; H NMR (600 MHz, DMSO-d6) δ: 10.30 (s, 1H,
2.1.8. Synthesis of N-(4-(N-(2-bromoethyl)-N-(2-chloro-
benzyl) sulfamoyl) phenyl) acetamide (5a)
NHCOCH3), 8.02 (t, J = 6.2 Hz, 1H, SO2NH), 7.74 (d, J =
8.8 Hz, 2H, Ph-2,6-H), 7.71 (d, J = 8.8 Hz, 2H, Ph-3,5-H),
7.27 (dd, J = 7.9, 5.9 Hz, 2H, 4-FPh-3,5-H), 7.10 (t, J = 8.8
Hz, 2H, 4-FPh-2,6-H), 3.94 (d, J = 6.2 Hz, 2H, 4-FPh-CH2),
2.09 (s, 3H, COCH3) ppm; 13C NMR (151 MHz, DMSO-d6)
δ: 169.4, 161.8, 143.2, 134.9, 134.5, 130.1, 128.1, 119.1,
115.5, 45.8, 24.6 ppm.
The mixture of 1,2-dibromoethane (0.340 g, 1.8 mmol),
compound 4a (0.513 g, 1.5 mmol) and potassium carbonate
(0.759 g, 5.5 mmol) was reacted in acetone (50 mL) at 50ºC
for 8 h. When the reaction was completed (monitored by
TLC, eluent, chloroform/ethyl acetate, 5/1, V/V), the residue
was extracted with chloroform (3 × 25 mL). Compound 5a
was prepared and purified as white solid. Yield: 82%; mp:
90–92ºC; IR (KBr) ν: 3371 (N−H), 3108, 3060 (aromatic
C−H), 2929, 2857 (aliphatic C−H), 1703 (C=O), 1591, 1529,
2.1.5. Synthesis of N-(4-(N-(4-chlorobenzyl) sulfamoyl)
phenyl) acetamide (4c)
Compound 4c was prepared according to the procedure
described for compound 4a starting from compound 3 (5.108
g, 23.8 mmol) and 1-chloro-4-(chloromethyl)benzene (3.124
g, 19.4 mmol). The pure product 4c was obtained as white
solid. Yield: 17%; mp: 189–191ºC; IR (KBr) ν: 3304 (N−H),
3103, 3040 (aromatic C−H), 2928, 2857 (aliphatic C−H),
1670 (C=O), 1593, 1530 (aromatic frame), 1328, 1154, 784
cm-1; 1H NMR (600 MHz, DMSO-d6) δ: 10.30 (s, 1H,
NHCOCH3), 8.05 (t, J = 6.4 Hz, 1H, SO2NH), 7.74 (d, J =
8.8 Hz, 2H, Ph-2, 6-H), 7.71 (d, J = 8.8 Hz, 2H, Ph-3,5-H),
7.34 (d, J = 8.3 Hz, 2H, 4-ClPh-3,5-H), 7.26 (d, J = 8.4 Hz,
2H, 4-ClPh-2,6-H), 3.95 (d, J = 6.4 Hz, 2H, 4-ClPh-CH2),
2.09 (s, 3H, COCH3) ppm; 13C NMR (151 MHz, DMSO-d6)
δ: 169.4, 143.2, 137.4, 134.8, 132.2, 129.9, 128.6, 128.1,
119.1, 45.8, 24.6 ppm.
1
1495 (aromatic frame), 1334, 1156, 752, 548 cm-1; H NMR
(600 MHz, DMSO-d6) δ: 10.38 (s, 1H, NHCOCH3), 7.81
(apparent s, 4H, Ph-H), 7.51 (dd, J = 7.0, 2.3 Hz, 1H, 2-
ClPh-3-H), 7.45 (dd, J = 7.2, 2.0 Hz, 1H, 2-ClPh-4-H), 7.36–
7.33 (m, 2H, 2-ClPh-5,6-H), 4.45 (s, 2H, 4-FPh-CH2), 3.49
(t, J = 7.3 Hz, 2H, NCH2CH2), 3.30 (t, J = 7.3 Hz, 2H,
NCH2CH2), 2.11 (s, 3H, COCH3) ppm; 13C NMR (151 MHz,
DMSO-d6) δ: 169.7, 144.0, 134.6, 132.9, 130.7, 130.3,
129.9, 128.8, 128.4, 127.8, 119.3, 50.7, 49.06, 30.4, 24.6
ppm; HRMS (TOF) found, m/z 444.9978 [M + H]+, calcd for
C17H19BrClN2O3S: 444.9983.
2.1.9.
Synthesis
of
N-(4-(N-(2-bromoethyl)-N-(4-
fluorobenzyl) sulfamoyl) phenyl) acetamide (5b)
Compound 5b was prepared according to the procedure
described for compound 5a starting from compound 4b
(0.307 g, 1.0 mmol) and 1,2-dibromoethane (0.434 g, 2.3
mmol). The pure product 5b was obtained as white solid.
Yield: 74%; mp: 132–134ºC; IR (KBr) ν: 3295 (N−H), 3102,
3047 (aromatic C−H), 2933, 2865 (aliphatic C−H), 1671
(C=O), 1590, 1536, 1509 (aromatic frame), 1340, 1160, 835,
2.1.6. Synthesis of N-(4-(N-(2, 4-dichlorobenzyl) sulfamoyl)
phenyl) acetamide (4d)
Compound 4d was prepared according to the procedure
described for compound 4a starting from compound 3 (3.007
g, 14.0 mmol) and 2,4-dichloro-1-(chloromethyl)benzene
(3.076 g, 14.4 mmol). The pure product 4d was obtained as
white solid. Yield: 3%; mp: 233–235ºC; IR (KBr) ν: 3300
(N−H), 3112, 3054 (aromatic C−H), 2925, 2858 (aliphatic
C−H), 1678 (C=O), 1593, 1528 (aromatic frame), 1338,
1153, 763 cm-1; 1H NMR (600 MHz, DMSO-d6) δ: 10.39 (s,
1H, NHCOCH3), 7.81 (apparent s, 4H, Ph-H), 7.62 (s, 1H,
SO2NH), 7.50–7.39 (m, 3H, 2,4-Cl2Ph-3,5,6-H), 4.31 (s, 2H,
2,4-Cl2Ph-CH2), 2.07 (s, 3H, COCH3) ppm; 13C NMR (151
MHz, DMSO-d6) δ: 169.4, 144.6, 140.5, 133.9, 130.8, 130.1,
130.0, 129.4, 119.1, 115.6, 115.3, 45.8, 24.6 ppm.
1
748, 611 cm-1; H NMR (600 MHz, DMSO-d6) δ: 10.37 (s,
1H, NHCOCH3), 7.81 (apparent s, 4H, Ph-H), 7.45–7.28 (m,
2H, 4-FPh-2,6-H), 7.18 (t, J = 8.4 Hz, 2H, 4-FPh-3,5-H),
4.31 (s, 2H, 4-FPh-CH2), 3.43–3.39 (t, 2H, NCH2CH2),
3.27–3.23 (t, 2H, NCH2CH2), 2.10 (s, 3H, COCH3) ppm; 13
C
NMR (151 MHz, DMSO-d6) δ: 169.5, 161.4, 143.9, 132.7,
130.8, 130.7, 128.7, 119.3, 115.8, 50.0, 49.1, 30.4, 24.6 ppm;
HRMS (TOF) found, m/z 429.0273 [M + H]+, calcd for
C17H19BrFN2O3S: 429.0278.
2.1.7. Synthesis of N-(4-(N-(3,4-dichlorobenzyl) sulfamoyl)
phenyl) acetamide (4e)
2.1.10.
Synthesis
of
N-(4-(N-(2-bromoethyl)-N-(4-
chlorobenzyl) sulfamoyl) phenyl) acetamide (5c)
Compound 4e was prepared according to the procedure
described for compound 4a starting from compound 3 (3.011
g, 14.1 mmol) and 3,4-dichloro-1-(chloromethyl)benzene
(2.709 g, 13.9 mmol). The pure product 4e was obtained as
white solid. Yield: 4%; mp: 183–185ºC; IR (KBr) ν: 3305
(N−H), 3103, 3049 (aromatic C−H), 2926, 2857 (aliphatic
Compound 5c was prepared according to the procedure
described for compound 5a starting from compound 4c
(0.515 g, 1.5 mmol) and 1,2-dibromoethane (0.361 g, 1.9
mmol). The pure product 5c was obtained as yellow syrup.
Yield: 70%; IR (KBr) ν: 3364 (N−H), 3104, 3042 (aromatic
C−H), 2928, 2857 (aliphatic C−H), 1702 (C=O), 1594, 1528,

Bioactivity Exploration of Sulfonamide-Derived Triazoles
Medicinal Chemistry, 2020, Vol. 16, No. 1 107
1
1492 (aromatic frame), 1326, 1153, 784, 611 cm-1; H NMR
(600 MHz, DMSO-d6) δ: 10.38 (s, 1H, NHCOCH3), 7.82
(apparent s, 4H, Ph-H), 7.43–7.40 (m, 2H, 4-ClPh-2,6-H),
7.37–7.34 (m, 2H, 4-ClPh-3,5-H), 4.33 (s, 2H, 4-FPh-CH2),
3.43 (t, J = 7.3 Hz, 2H, NCH2CH2), 3.27 (t, J = 7.3 Hz, 2H,
NCH2CH2), 2.10 (s, 3H, COCH3) ppm; 13C NMR (151 MHz,
DMSO-d6) δ: 169.5, 144.0, 132.8, 132.6, 130.5, 128.9,
128.7, 128.5, 119.3, 51.6, 49.1, 30.4, 24.6 ppm; HRMS
V/V), the residue was extracted with chloroform (3 × 20
mL). Compound 6a was prepared and purified as white
solid. Yield: 67%; mp: 179–181ºC; IR (KBr) ν: 3302 (N−H),
3093, 3040, 3003 (aromatic C−H), 2942, 2869, 2802 (ali-
phatic C−H), 1691 (C=O), 1592, 1541, 1512 (aromatic
1
frame), 1317, 1151, 992, 732 cm-1; H NMR (600 MHz,
DMSO-d6) δ: 10.33 (s, 1H, NHCOCH3), 8.28 (s, 1H, TRA
C5-H), 7.84 (s, 1H, TRA C3-H), 7.77 (d, J = 8.3 Hz, 2H, Ph-
2,6-H), 7.73 (d, J = 8.6 Hz, 2H, Ph-3,5-H), 7.36–7.26 (m,
2H, NCH2Ph-2,6-H), 7.14 (m, 3H, NCH2Ph-3,4,5-H), 4.32
(s, 2H, NCH2Ph), 4.21 (t, J = 6.2 Hz, 2H, NCH2CH2), 3.51
(t, J = 6.2 Hz, 2H, NCH2CH2), 2.10 (s, 3H, COCH3) ppm;
13C NMR (151 MHz, DMSO-d6) δ: 169.5, 151.9, 144.7,
132.3, 131.2, 131.1, 128.7, 124.9, 123.7, 123.6, 119.2, 48.2,
48.0, 46.4, 24.6 ppm; HRMS (TOF) found, m/z 400.1435 [M
+ H]+, calcd for C19H22N5O3S: 400.1438.
(TOF) found, m/z 444.9981 [M
C17H19BrClN2O3S: 444.9983.
+
H]+, calcd for
2.1.11. Synthesis of N-(4-(N-(2-bromoethyl)-N-(2,4-di-
chlorobenzyl) sulfamoyl) phenyl) acetamide (5d)
Compound 5d was prepared according to the procedure
described for compound 5a starting from compound 4d
(0.110 g, 0.3 mmol) and 1,2-dibromoethane (0.081 g, 0.4
mmol). The pure product 5d was obtained as a white solid.
Yield: 89%; mp: 164–166ºC; IR (KBr) ν: 3300 (N−H), 3113,
3055 (aromatic C−H), 2926, 2857 (aliphatic C−H), 1670
(C=O), 1594, 1538, 1502, 1474 (aromatic frame), 1343,
2.1.14. Synthesis of N-(4-(N-(2-(1H-1,2,4-triazol-1-Yl)
ethyl)-N-(2-fluorobenzyl) sulfamoyl) phenyl) acetamide
(6b)
1159, 1095, 763 cm-1; H NMR (600 MHz, DMSO-d6) δ:
1
Compound 6b was synthesized according to the experi-
mental procedure reported for compound 6a, starting from
compound 11 (0.066 g, 0.2 mmol) and 1-(chloromethyl)-2-
fluorobenzene (0.030 g, 0.2 mmol). The pure product 6b was
obtained as white solid. Yield: 81%; mp: 175–177ºC; R
(KBr) ν: 3303 (N−H), 3094, 3044, 3004 (aromatic C−H),
2870, 2802 (aliphatic C−H), 1692 (C=O), 1592, 1541 (aro-
10.38 (s, 1H, NHCOCH3), 7.87–7.79 (apparent s, 4H, Ph-H),
7.41–7.36 (m, 1H, 2,4-Cl2Ph-3-H), 7.24 (dd, J = 8.7 Hz, 1H,
2,4-Cl2Ph-5-H), 7.19–7.11 (m, 1H, 2,4-Cl2Ph-6-H), 4.36 (m,
4H, 2,4-Cl2Ph-CH2, NCH2CH2), 3.31 (m, 2H, NCH2CH2),
2.12 (s, 3H, COCH3) ppm; 13C NMR (151 MHz, DMSO-d6)
δ: 169.5, 144.1, 135.8, 133.3, 132.0, 130.3, 128.9, 128.8,
128.4, 127.5, 119.4, 52.2, 50.0, 49.8, 24.6 ppm; HRMS
1
matic frame), 1343, 1149, 760, 609 cm-1; H NMR (600
(TOF) found, m/z 478.9597 [M
C17H18BrCl2N2O3S: 478.9593.
+
H]+, calcd for
MHz, DMSO-d6) δ: 10.34 (s, 1H, NHCOCH3), 8.28 (s, 1H,
TRA C5-H), 7.84 (s, 1H, TRA C3-H), 7.77 (d, J = 8.8 Hz,
2H, Ph-2,6-H), 7.73 (d, J = 8.7 Hz, 2H, Ph-3,5-H), 7.34 (dd,
J = 6.6 Hz, 1H, 2-FPh-3-H), 7.28 (t, J = 7.4 Hz, 1H, 2-FPh-
4-H), 7.14 (t, J = 8.1 Hz, 2H, 2-FPh-5,6-H), 4.32 (s, 2H, 2-
FPh-CH2), 4.21 (t, J = 6.4 Hz, 2H, NCH2CH2), 3.51 (t, J =
6.4 Hz, 2H, NCH2CH2), 2.10 (s, 3H, COCH3) ppm; 13C
NMR (151 MHz, DMSO-d6) δ: 169.3, 156.4, 148.3, 148.2,
141.2, 127.3, 126.9, 125.2, 118.9, 118.0, 111.8, 108.7, 99.0,
55.6, 37.6, 35.2, 26.8 ppm; HRMS (TOF) found, m/z
418.1347 [M + H]+, calcd for C19H20FN5O3S: 418.1344.
2.1.12. Synthesis of N-(4-(N-(2-bromoethyl)-N-(3,4-
dichlorobenzyl) sulfamoyl) phenyl) acetamide (5e)
Compound 5e was prepared according to the procedure
described for compound 5a starting from compound 4e
(0.150 g, 0.4 mmol) and 1,2-dibromoethane (0.125 g, 0.7
mmol). The pure product 5e was obtained as yellow syrup.
Yield: 79%; IR (KBr) ν: 3318 (N−H), 3105, 3054 (aromatic
C−H), 2925, 2858 (aliphatic C−H), 1678 (C=O), 1591, 1530,
1
1470 (aromatic frame), 1368, 1156, 746, 612 cm-1; H NMR
2.1.15. Synthesis of N-(4-(N-(2-(1h-1,2,4-triazol-1-Yl)
ethyl)-N-(2-chlorobenzyl) sulfamoyl) phenyl) acetamide
(6c)
(600 MHz, DMSO-d6) δ: 10.38 (s, 1H, NHCOCH3), 7.81
(apparent s, 4H, Ph-H), 7.62 (d, J = 8.3 Hz, 1H, 2,3-Cl2Ph-4-
H), 7.52 (d, J = 2.0 Hz, 1H, 2,3-Cl2Ph-5-H), 7.34 (dd, J =
8.3, 2.0 Hz, 1H, 2,3-Cl2Ph-6-H), 4.34 (s, 2H, 2,3-Cl2Ph-
CH2), 3.47 (t, J = 7.1 Hz, 2H, NCH2CH2), 3.36 (t, J = 6.8 Hz,
2H, NCH2CH2), 2.10 (s, 3H, COCH3) ppm; 13C NMR (151
MHz, DMSO-d6) δ: 169.6, 144.1, 138.8, 132.5, 131.5, 131.1,
130.7, 130.5, 128.8, 128.8, 119.3, 51.1, 50.6, 30.6, 24.6 ppm;
HRMS (TOF) found, m/z 478.9589 [M + H]+, calcd for
C17H18BrCl2N2O3S: 478.9593.
A solution of 1H-1,2,4-triazole (0.096 g, 1.4 mmol) and
potassium carbonate (0.233 g, 1.7 mmol) was reacted in ace-
tonitrile (25 mL) at 70ºC for 0.5 h. Compound 5a (0.463 g,
1.4 mmol) was added to the mixture at room temperature,
and then the system was stirred at 70ºC. When the reaction
was completed (monitored by TLC, eluent, chloro-
form/methanol, 20/1, V/V), the residue extracted with chlo-
roform (3 × 20 mL). Compound 6c was provided and puri-
fied as white solid. Yield: 56%; mp: 187–189ºC; R (KBr) ν:
3301 (N−H), 3103, 3043 (aromatic C−H), 2865, 2792 (ali-
phatic C−H), 1689 (C=O), 1590, 1532 (aromatic frame),
2.1.13. Synthesis of N-(4-(N-(2-(1H-1,2,4-triazol-1-yl)
ethyl)-n-benzylsulfamoyl) phenyl) acetamide (6a)
1
1341, 1163, 802, 611 cm-1; H NMR (600 MHz, DMSO-d6)
The acetone solution of compound 11 (0.063 g, 1.5
mmol) and potassium carbonate (0.026 g, 0.2 mmol) was
reacted at 70ºC for 0.5 h. The benzyl chloride (0.024 g, 1.5
mmol) was added at room temperature, and then the mixture
was stirred at 60ºC. When the reaction came to the end
(monitored by TLC, eluent, chloroform/methanol, 15/1,
δ: 10.39 (s, 1H, NHCOCH3), 8.28 (s, 1H, TRA C5-H), 7.84
(s, 1H, TRA C3-H), 7.81 (d, J = 9.1 Hz, 2H, Ph-2,6-H), 7.78
(d, J = 9.1 Hz, 2H, Ph-3,5-H), 7.41 (d, J = 8.0 Hz, 1H, 2-
ClPh-3-H), 7.33–7.26 (m, 3H, 2-ClPh-4,5,6-H), 4.34 (s, 2H,
2-ClPh-CH2), 4.20 (t, J = 6.4 Hz, 2H, NCH2CH2), 3.55 (t, J =

108 Medicinal Chemistry, 2020, Vol. 16, No. 1
He et al.
6.4 Hz, 2H, NCH2CH2), 2.10 (s, 3H, COCH3) ppm; 13C
NMR (151 MHz, DMSO-d6) δ: 169.6, 151.9, 144.7, 144.0,
134.2, 132.8, 132.0, 130.4, 129.9, 129.8, 128.9, 127.7, 119.3,
50.5, 48.6, 48.2, 24.6 ppm; HRMS (TOF) found, m/z
434.1043 [M + H]+, calcd for C19H20ClN5O3S: 434.1048.
DMSO-d6) δ: 10.37 (s, 1H, NHCOCH3), 8.30 (s, 1H, TRA
C5-H), 7.82 (s, 1H, TRA C3-H), 7.80 (apparent s, 4H, Ph-H),
7.54 (s, 1H, 2,4-Cl2Ph-3-H), 7.37 (d, 1H, 2,4-Cl2Ph-5-H)7.33
(d, 1H, 2,4-Cl2Ph-6-H), 4.31 (s, 2H, 2,4-Cl2Ph-CH2), 4.23 (t,
J = 6.2 Hz, 2H, NCH2CH2), 3.55 (t, J = 6.1 Hz, 2H,
NCH2CH2), 2.11 (s, 1H, COCH3) ppm; 13C NMR (151 MHz,
DMSO-d6) δ: 169.6, 151.9, 144.7, 144.1, 133.7, 133.6,
133.4, 131.8, 129.3, 128.9, 127.9, 119.3, 118.5, 50.2, 48.8,
48.3, 24.6 ppm; HRMS (TOF) found, m/z 468.0653 [M +
H]+, calcd for C19H19Cl2N5O3S: 468.0658.
2.1.16. Synthesis of N-(4-(N-(2-(1h-1,2,4-triazol-1-yl)
ethyl)-N-(4-fluorobenzyl) sulfamoyl) phenyl) acetamide
(6d)
Compound 6d was synthesized according to the experi-
mental procedure reported for compound 6c, starting from
compound 5b (0.390 g, 0.9 mmol) and 1H-1, 2,4 -triazole
(0.065 g, 0.9 mmol). The pure product 6d was obtained as
white solid. Yield: 78%; mp: 177–179ºC; R (KBr) ν: 3303
(N−H), 3097, 3036 (aromatic C−H), 2996, 2944, 2873, 2804
(aliphatic C−H), 1692 (C=O), 1591, 1543, 1509 (aromatic
2.1.19. Synthesis of N-(4-(N-(2-(1h-1,2,4-triazol-1-yl)
Ethyl)-N-(3,4-Dichlorobenzyl) Sulfamoyl) Phenyl) Aceta-
mide (6g)
Compound 6g was synthesized according to the experi-
mental procedure reported for compound 6c, starting from
compound 5e (0.193 g, 0.4 mmol) and 1H-1,2,4 -triazole
(0.051 g, 0.7 mmol). The pure product 6g was obtained as
white solid. Yield: 73%; mp: 195–197ºC; R (KBr) ν: 3394
(N−H), 3084, 3018 (aromatic C−H), 2960, 2923, 2887 (ali-
phatic C−H), 1687 (C=O), 1590, 1542, 1511 (aromatic
1
frame), 1315, 1149, 797, 610 cm-1; H NMR (600 MHz,
DMSO-d6) δ: 10.37 (s, 1H, NHCOCH3), 8.24 (s, 1H, TRA
C5-H), 7.85 (s, 1H, TRA C3-H), 7.79 (d, J = 8.9 Hz, 2H, Ph-
2,6-H), 7.76 (d, J = 8.9 Hz, 2H, Ph-3,5-H), 7.26 (d, J = 8.5
Hz, 2H, 4-FPh-2,6-H), 7.13 (d, J = 8.5 Hz, 2H, 4-FPh-3,5-
H), 4.22 (s, 2H, 4-FPh-CH2), 4.15 (t, J = 6.4 Hz, 2H,
NCH2CH2), 3.46 (t, J = 6.4 Hz, 2H, NCH2CH2), 2.10 (s, 3H,
COCH3) ppm; 13C NMR (151 MHz, DMSO-d6) δ: 169.5,
161.3, 151.9, 144.7, 143.9, 132.4, 130.6, 128.7, 119.3, 115.8,
115.7, 51.7, 49.1, 48.0, 24.9 ppm; HRMS (TOF) found, m/z
418.1347 [M + H]+, calcd for C19H20FN5O3S: 418.1344.
1
frame), 1332, 1156, 828, 612 cm-1; H NMR (600 MHz,
DMSO-d6) δ: 10.38 (s, 1H, NHCOCH3), 8.29 (s, 1H, TRA
C5-H), 7.83 (s, 1H, TRA C3-H), 7.79 (apparent s, 4H, Ph-H),
7.56 (d, J = 8.3 Hz, 1H, 2,3-Cl2Ph-4-H), 7.35 (d, J = 2.0 Hz,
1H, 2,3-Cl2Ph-5-H), 7.20 (dd, J = 8.3, 2.0 Hz, 1H, 2,3-Cl2Ph-
6-H), 4.24 (s, 2H, 2,3-Cl2Ph-CH2), 4.23 (t, J = 6.2 Hz, 2H,
NCH2CH2), 3.52 (t, J = 6.3 Hz, 2H, NCH2CH2), 2.11 (s, 1H,
COCH3) ppm; 13C NMR (151 MHz, DMSO-d6) δ: 169.5,
162.9, 151.8, 144.7, 144.1, 138.4, 131.5, 131.0, 130.3, 128.8,
128.7, 127.3, 119.3, 51.4, 49.1, 48.1, 24.6 ppm; HRMS
2.1.17. Synthesis of N-(4-(N-(2-(1h-1,2,4-triazol-1-yl)
ethyl)-N-(4-chlorobenzyl) sulfamoyl) phenyl) acetamide
(6e)
(TOF) found, m/z 468.0656 [M
C19H19Cl2N5O3S: 468.0658.
+
H]+, calcd for
Compound 6e was synthesized according to the experi-
mental procedure reported for compound 6c, starting from
compound 5c (0.390 g, 0.8 mmol) and 1H-1,2,4-triazole
(0.064 g, 0.9 mmol). The pure product 6e was obtained as
white solid. Yield: 62%; mp: 195–197ºC; R (KBr) ν: 3300
(N−H), 3096, 3036 (aromatic C−H), 2997, 2942, 2870, 2804
(aliphatic C−H), 1690 (C=O), 1591, 1543, 1515 (aromatic
2.1.20. Synthesis of N-(2-(1h-1,2,4-triazol-1-yl)ethyl)-4-
amino-N-benzylbenzenesulfonamide (7a)
0.5 mL 2 mol/L sodium hydroxide solution was added to
a solution of compound 6a in ethanol 15 mL. The mixture
was refluxed for 10 h (monitored by TLC, eluent, ace-
tone/petroleum ether, 1/1, V/V). After cooling to the room
temperature, the solvent was evaporated and the residue was
treated with water (30 mL) and extracted with chloroform (3
× 30 mL). The organic layers were combined, dried over
anhydrous sodium sulfate and concentrated in vacuo to give
the deprotected compound 7a as white solid. Yield: 92%;
mp: 154–156ºC; R (KBr) ν: 3453, 3365 (N−H), 3003 (aro-
matic C−H), 2924, 2856 (aliphatic C−H), 1592, 1503 (aro-
1
frame), 1317, 1151, 799, 610 cm-1; H NMR (600 MHz,
DMSO-d6) δ: 10.37 (s, 1H, NHCOCH3), 8.25 (s, 1H, TRA
C5-H), 7.84 (s, 1H, TRA C3-H), 7.78 (apparent s, 4H, Ph-H),
7.37 (d, J = 8.3 Hz, 2H, 4-ClPh-3,5-H), 7.24 (d, J = 8.3 Hz,
2H, 4-ClPh-2,6-H), 4.23 (s, 2H, 4-ClPh-CH2), 4.16 (t, J = 6.4
Hz, 2H, NCH2CH2), 3.47 (t, J = 6.4 Hz, 2H, NCH2CH2),
2.10 (s, 3H, COCH3) ppm; 13C NMR (151 MHz, DMSO-d6)
δ: 169.5, 151.9, 144.7, 143.9, 136.0, 132.8, 132.35, 130.4,
128.9, 128.7, 119.3, 51.8, 49.1, 48.1, 24.6 ppm; HRMS
1
matic frame), 1324, 1151, 733, 550 cm-1; H NMR (600
(TOF) found, m/z 434.1045 [M
C19H20ClN5O3S: 434.1048.
+
H]+, calcd for
MHz, CDCl3) δ: 7.84 (s, 1H, TRA C5-H), 7.77 (s, 1H, TRA
C3-H), 7.61 (d, J = 8.4 Hz, 2H, Ph-2,6-H), 7.28 (m, 3H,
NCH2Ph-2,5,6-H), 7.17–7.11 (m, 2H, NCH2Ph-3,4-H), 6.71
(d, J = 8.5 Hz, 2H, Ph-3,5-H), 4.18 (t, J = 6.0 Hz, 2H,
NCH2CH2), 4.08 (s, 2H, NCH2Ph), 3.43 (t, J = 6.3 Hz, 2H,
NCH2CH2) ppm; 13C NMR (151 MHz, CDCl3) δ: 152.1,
150.9, 143.7, 135.8, 129.5, 128.8, 128.6, 128.1, 126.7, 114.2,
53.8, 50.8, 47.7 ppm; HRMS (TOF) found, m/z 358.1335 [M
+ H]+, calcd for C17H19N5O2S: 358.1332.
2.1.18. Synthesis of N-(4-(N-(2-(1h-1,2,4-triazol-1-yl)
ethyl)-N-(2,4-dichlorobenzyl) sulfamoyl) phenyl) acetamide
(6f)
Compound 6f was synthesized according to the experi-
mental procedure reported for compound 6c, starting from
compound 5d (0.457 g, 0.9 mmol) and 1H-1,2,4 -triazole
(0.106 g, 1.54 mmol). The pure product 6f was obtained as
white solid. Yield: 69%; mp: 199–201ºC; R (KBr) ν: 3306
(N−H), 3096, 3035 (aromatic C−H), 2999, 2971, 2804 (ali-
phatic C−H), 1694 (C=O), 1591, 1542, 1514 (aromatic
2.1.21. Synthesis of N-(2-(1h-1,2,4-triazol-1-yl) ethyl)-4-
amino-N-(2-fluorobenzyl) benzenesulfonamide (7b)
1
frame), 1341, 1152, 792, 611 cm-1; H NMR (600 MHz,
Compound 7b was obtained as white solid. Yield: 90%;
mp: 161–163ºC; IR (KBr) ν: 3453, 3367 (N−H), 3109 (aro-

Bioactivity Exploration of Sulfonamide-Derived Triazoles
Medicinal Chemistry, 2020, Vol. 16, No. 1 109
2.1.25. Synthesis of N-(2-(1h-1,2,4-triazol-1-yl) ethyl)-4-
amino-N-(2,4-dichlorobenzyl) benzenesulfonamide (7f)
matic C−H), 2950, 2924, 2854 (aliphatic C−H), 1592, 1502
(aromatic frame), 1117, 616 cm-1; 1H NMR (600 MHz,
CDCl3) δ: 7.91 (s, 1H, TRA C5-H), 7.74 (s, 1H, TRA C3-H),
7.57 (d, J = 8.5 Hz, 2H, Ph-2,6-H), 7.23 (m, 2H, 2-FPh-3,4-
H), 7.08 (m, 1H, 2-FPh-6-H), 6.98 (t, J = 9.1 Hz, 1H, 2-FPh-
5-H), 6.69 (d, J = 8.5 Hz, 2H, Ph-3,5-H), 4.27 (t, J = 6.2 Hz,
2H, NCH2CH2), 4.20 (s, 2H, 2-FPh-CH2), 3.46 (t, J = 6.2 Hz,
2H, NCH2CH2) ppm; 13C NMR (151 MHz, CDCl3) δ: 160.0,
152.1, 150.9, 143.7, 131.1, 129.9, 129.9, 129.6, 124.6, 115.6,
115.4, 114.2, 50.8, 48.9, 48.1 ppm; HRMS (TOF) found, m/z
376.1242 [M + H]+, calcd for C17H18FN5O2S: 376.1238.
Compound 7f was obtained as yellow syrup. Yield: 94%;
R (KBr) ν: 3430 (N−H), 3136 (aromatic C−H), 2958, 2925,
2858 (aliphatic C−H), 1599, 1515 (aromatic frame), 1099,
1
805, 469 cm-1; H NMR (600 MHz, DMSO-d6) δ: 8.29 (s,
1H, TRA C5-H), 7.82 (s, 1H, TRA C3-H), 7.53 (d, J = 1.8
Hz, 1H, 2,4-Cl2Ph-3-H), 7.49 (d, J = 8.6 Hz, 2H, Ph-2,6-H),
7.37–7.28 (m, 2H, 2,4-Cl2Ph-5,6-H), 6.67 (d, J = 8.5 Hz, 2H,
Ph-3,5-H), 6.13 (s, 2H, NH2), 4.23 (t, J = 6.2 Hz, 2H,
NCH2CH2), 4.21 (s, 2H, 2,4-Cl2Ph-CH2), 3.47 (t, J = 6.2 Hz,
2H, NCH2CH2) ppm; 13C NMR (151 MHz, DMSO-d6) δ:
153.9, 151.8, 144.7, 134.0, 133.6, 133.2, 131.7, 129.8, 129.2,
127.8, 122.7, 113.4, 50.3, 48.8, 48.4 ppm; HRMS (TOF)
2.1.22. Synthesis of N-(2-(1h-1, 2,4-triazol-1-yl) ethyl)-4-2-
chlorobenzyl) benzenesulfonamide (7c)
Compound 7c was obtained as light brown syrup. Yield:
91%; IR (KBr) ν: 3453, 3366 (N−H), 3128, 3034 (aromatic
C−H), 2914, 2859 (aliphatic C−H), 1591, 1504 (aromatic
found, m/z 448.0377 [M
C17H17Cl2N5NaO2S: 448.0372.
+
Na]+, calcd for
1
frame), 1326, 1153, 881, 555 cm-1; H NMR (600 MHz,
2.1.26. Synthesis of N-(2-(1h-1,2,4-triazol-1-yl) ethyl)-4-
amino-N-(3,4-dichlorobenzyl) benzenesulfonamide (7g)
DMSO-d6) δ: 8.28 (s, 1H, TRA C5-H), 7.84 (s, 1H, TRA C3-
H), 7.49 (d, J = 8.7 Hz, 2H, Ph-2,6-H), 7.40 (dd, J = 5.8, 3.5
Hz, 1H, 2-ClPh-3-H), 7.33–7.24 (m, 3H, 2-ClPh-4,5,6-H),
6.66 (d, J = 8.7 Hz, 2H, Ph-3,5-H), 4.24 (s, 2H, 2-ClPh-
CH2), 4.19 (t, J = 6.5 Hz, 2H, NCH2CH2), 3.47 (t, J = 6.5 Hz,
2H, NCH2CH2) ppm; 13C NMR (151 MHz, DMSO-d6) δ:
153.8, 151.9 144.7, 134.6, 132.7, 130.3, 129.8, 129.7, 129.6,
127.68, 123.0, 113.4, 50.5, 49.1, 48.3 ppm; HRMS (TOF)
Compound 7g was obtained as white solid. Yield: 89%;
mp: 157-159ºC; IR (KBr) ν: 3458, 3330 (N−H), 3145 (aro-
matic C−H), 2964, 2920, 2863 (aliphatic C−H), 1592, 1502
1
(aromatic frame), 1323, 1151, 874, 548 cm-1; H NMR (600
MHz, CDCl3) δ: 7.95 (s, 1H, TRA C5-H), 7.80 (s, 1H, TRA
C3-H), 7.58 (d, J = 8.5 Hz, 2H, Ph-2,6-H), 7.32 (d, J = 8.2
Hz, 1H, 3,4-Cl2Ph-5-H), 7.11 (s, 1H, 3,4-Cl2Ph-2-H), 6.93
(d, J = 8.1 Hz, 1H, 3,4-Cl2Ph-6-H), 6.71 (d, J = 8.5 Hz, 2H,
Ph-3,5-H), 4.29 (t, J = 6.0 Hz, 2H, NCH2CH2), 3.97 (s, 2H,
3,4-Cl2Ph-CH2), 3.45 (t, J = 6.0 Hz, 2H, NCH2CH2) ppm; 13C
NMR (151 MHz, CDCl3) δ: 152.2, 151.0, 144.2, 137.8,
134.3, 134.1, 129.8, 129.5, 129.0, 128.5, 126.4, 114.2, 53.1,
49.1, 47.6 ppm; HRMS (TOF) found, m/z 426.0557 [M +
H]+, calcd for C17H17Cl2N5O2S: 426.0553.
found, m/z 414.0766 [M
C17H18ClN5NaO2S: 414.0762.
+
Na]+, calcd for
2.1.23. Synthesis of N-(2-(1h-1,2,4-triazol-1-yl) ethyl)-4-
amino-N-(4-fluorobenzyl) benzenesulfonamide (7d)
Compound 7d was obtained as white solid. Yield: 92%;
mp: 144-146ºC; R (KBr) ν: 3450, 3316 (N−H), 3056 (aro-
matic C−H), 2966, 2906, 2859 (aliphatic C−H), 1594, 1506
1
(aromatic frame), 1322, 1150, 733, 551 cm-1; H NMR (600
2.1.27. Synthesis of tert-butyl (4-acetamidophenyl) Sul-
fonyl) carbamate (8)
MHz, DMSO-d6) δ: 8.23 (s, 1H, TRA C5-H), 7.85 (s, 1H,
TRA C3-H), 7.46 (d, J = 8.7 Hz, 2H, Ph-2,6-H), 7.24 (m, 2H,
4-FPh-2,6-H), 7.12 (m, 2H, 4-FPh-3,5-H), 6.64 (d, J = 8.7
Hz, 2H, Ph-3,5-H), 6.09 (s, 2H, NH2), 4.14 (t, J = 6.5 Hz,
2H, NCH2CH2), 4.12 (s, 2H, 4-FPh-CH2), 3.38 (t, J = 6.5 Hz,
2H, NCH2CH2) ppm; 13C NMR (151 MHz, DMSO-d6) δ:
161.2, 153.7, 151.8, 144.6, 133.4, 130.6, 130.5, 129.6, 115.6,
113.3, 51.8, 49.0, 48.2 ppm; HRMS (TOF) found, m/z
376.1254 [M + H]+, calcd for C17H18FN5O2S: 376.1238.
To solution of the compound 3 (0.214 g, 1.1 mmol) in di-
chloromethane (20 mL) at 0oC was added triethylamine (0.15
mL, 1.1 mmol), followed by 4-(dimethylamino)-pyridin
(0.010 g, 0.08 mmol). The di-tertbutyl dicarbonate (0.327 g,
1.5 mmol) was added to the reaction mixture and stirred at
o
0 C for 0.5 h, and then transferred the system to room tem-
perature stirring for another 13 h. After the reaction came to
the end (monitored by TLC, eluent, chloroform/methanol =
15/1, V/V), concentrated and chromatography (eluent, di-
chloromethane/methanol = 4/1, V/V) afforded the intermedi-
ates 8 as white solid. Yield: 71%; mp: 137–139ºC; IR (KBr)
ν: 3358 (N−H), 3117 (aromatic C−H), 2980, 2934, 2854
(aliphatic C−H), 1676 (C=O), 1592, 1530 (aromatic frame),
2.1.24. Synthesis of N-(2-(1h-1,2,4-triazol-1-yl) ethyl)-4-
amino-N-(4-chlorobenzyl) benzenesulfonamide (7e)
Compound 7e was obtained as white solid. Yield: 91%;
mp: 148–152ºC; R (KBr) ν: 3479, 3382 (N−H), 3132, 3101
(aromatic C−H), 2961, 2922, 2857 (aliphatic C−H), 1594,
1
1247, 1151, 739, 613 cm-1; H NMR (600 MHz, DMSO-d6)
1
1503 (aromatic frame), 1318, 1145, 875, 546 cm-1; H NMR
δ: 11.47 (s, 1H, SO2NH), 10.38 (s, 1H, NHCOCH3), 7.80
(apparent s, 4H, Ph-H), 2.09 (s, 3H, COCH3), 1.29 (s, 9H,
Boc-H) ppm; 13C NMR (151 MHz, DMSO-d6) δ: 169.6,
150.3, 144.1, 133.6, 129.1, 118.8, 82.5, 28.0, 24.6 ppm;
HRMS (TOF) found, m/z 315.1006 [M + H]+, calcd for
C13H19N2O5S: 315.1009.
(600 MHz, CDCl3) δ: 7.91 (s, 1H, TRA C5-H), 7.78 (s, 1H,
TRA C3-H), 7.59 (d, J = 8.4 Hz, 2H, Ph-2,6-H), 7.24 (d, J =
8.1 Hz, 2H, 4-ClPh-3,5-H), 7.04 (d, J = 8.0 Hz, 2H, 4-ClPh-
2,6-H), 6.71 (d, J = 8.4 Hz, 2H, Ph-3,5-H), 4.24 (t, J = 6.1
Hz, 2H, NCH2CH2), 4.01 (s, 2H, 4-ClPh-CH2), 3.42 (t, J =
6.1 Hz, 2H, NCH2CH2) ppm; 13C NMR (151 MHz, CDCl3) δ:
152.2, 151.0, 144.2, 134.3, 134.1, 129.8, 129.5, 129.0, 126.4,
114.2, 53.1, 49.1, 47.6 ppm; HRMS (TOF) found, m/z
414.0765 [M + Na]+, calcd for C17H18ClN5NaO2S: 414.0762.
2.1.28. Synthesis of tert-butyl (4-acetamidophenyl) Sul-
fonyl) (tert-butyl) carbamate (9)
Compound 9 was obtained as white solid from procedure
for the preparation of compound 8. Yield: 28%; mp: 130–

110 Medicinal Chemistry, 2020, Vol. 16, No. 1
He et al.
132 oC; IR (KBr) ν: 3302 (N−H), 3120, 3059 (aromatic
C−H), 2982, 2934 (aliphatic C−H), 1675 (C=O), 1596, 1542
(aromatic frame), 1345, 1143, 623 cm-1; 1H NMR (600 MHz,
DMSO-d6) δ: 10.36 (s, 1H, NHCOCH3), 7.89 (d, J = 8.8 Hz,
2H, Ph-2,6-H), 7.79 (d, J = 8.8 Hz, 2H, Ph-3,5-H), 2.09 (s,
3H, COCH3), 1.45 (s, 9H, N(CH3)3), 1.40 (s, 9H, Boc-H)
ppm; 13C NMR (151 MHz, DMSO-d6) δ: 168.9, 155.3,
143.9, 133.2, 128.9, 118.0, 80.4, 49.8, 28.9, 24.3 ppm;
HRMS (TOF) found, m/z 371.1638 [M + H]+, calcd for
C17H27N2O5S: 371.1635.
1541, 1510 (aromatic frame), 1357, 1162, 633 cm-1; 1H
NMR (600 MHz, DMSO-d6) δ: 10.40 (s, 1H, NHCOCH3),
8.46 (s, 1H, TRA C5-H), 7.98 (s, 1H, TRA C3-H), 7.82 (d, J
= 9.0 Hz, 2H, Ph-2,6-H), 7.79 (d, J = 8.8 Hz, 2H, Ph-3,5-H),
4.49 (t, J = 5.9 Hz, 2H, NCH2CH2), 4.16 (t, J = 5.9 Hz, 2H,
NCH2CH2), 2.10 (s, 3H), 1.21 (s, 9H, Boc-H) ppm; 13C
NMR (151 MHz, DMSO-d6) δ: 169.6, 152.0, 150.5, 144.8,
144.5, 133.0, 129.5, 118.7, 84.5, 48.8, 46.6, 27.8, 24.6 ppm;
HRMS (TOF) found, m/z 409.1425 [M + H]+, calcd for
C17H23N5O5S: 409.1420.
2.1.29. Synthesis of tert-butyl (4-acetamidophenyl) Sul-
fonyl) (2-bromoethyl) carbamate (10)
2.1.32. Synthesis of N-(2-(1h-1,2,4-triazol-1-yl) ethyl)-4-
aminobenzenesulfonamide (13)
The compound 8 (3.314 g, 10.5 mmol) and potassium
carbonate (2.170 g, 15.7 mmol) in acetonitrile (100 mL) was
stirred at 60oC for 2 h, followed by the addition of 1,2-
dibromoethane (4.0 mL, 19.1 mmol), and then the reaction
system was stirred at 70 oC for about 10 h. After the reaction
came to the end (monitored by TLC, eluent, dichloro-
methane/methanol = 15: 1, V/V), the solvent was evaporated
and the residue was extracted with ethyl acetate (3 × 50 mL).
The organic extracts were collected and then dried over an-
hydrous sodium sulfate and purified by silica gel column
chromatography (eluent, petroleum ether/ethyl acetate = 4/1,
V/V) to afford white solid of intermediate 10. Yield: 64%;
The white solid of target product 13 was obtained accord-
ing to the experimental procedure reported for compound 7a,
starting from compound 11 (0.052g, 0.2 mmol). Yield: 98%;
mp: 161–163ºC; IR (KBr) ν: 3446, 3355 (N−H), 3114 (aro-
matic C−H), 2955, 2923, 2853 (aliphatic C−H), 1596, 1503
(aromatic frame), 1299, 1145, 688 cm-1; 1H NMR (600 MHz,
DMSO-d6) δ: 8.41 (s, 1H, TRA C5-H), 7.94 (s, 1H, TRA C3-
H), 7.39 (d, J = 8.5 Hz, 2H, Ph-2,6-H), 7.33 (s, 1H, SO2NH),
6.61 (d, J = 8.6 Hz, 2H, Ph-3,5-H), 5.94 (s, 2H, NH2), 4.20
(t, J = 6.2 Hz, 2H, NCH2CH2), 3.07 (t, J = 6.1 Hz, 2H,
NCH2CH2) ppm; 13C NMR (151 MHz, DMSO-d6) δ: 153.1,
151.9, 144.8, 128.9, 125.5, 113.2, 48.9, 42.4 ppm; HRMS
o
mp: 150–152 C; IR (KBr) ν: 3314 (N−H), 3106, 3048 (aro-
(TOF) found, m/z 290.0689 [M
C10H13FN5O2S: 290.2967.
+
H]+, calcd for
matic C−H), 2982, 2934 (aliphatic C−H), 1674 (C=O), 1596,
1
1534 (aromatic frame), 1352, 1159, 731,565 cm-1; H NMR
(600 MHz, CDCl3) δ: 7.86 (d, J = 8.7 Hz, 2H, Ph-2,6-H),
7.68 (d, J = 8.3 Hz, 2H, Ph-3,5-H), 4.16 (t, J = 7.4 Hz, 2H,
NCH2CH2), 3.59 (t, J = 7.4 Hz, 2H, NCH2CH2), 2.12 (s, 3H,
COCH3), 1.38 (s, 9H, Boc-H) ppm; 13C NMR (151 MHz,
CDCl3) δ: 168.7, 150.6, 142.8, 134.2, 129.4, 118.8, 85.1,
47.7, 28.9, 27.9, 24.7 ppm; HRMS (TOF) found, m/z
421.0429 [M + H]+, calcd for C15H22BrN2O5S: 421.0427.
3. RESULTS AND DISCUSSION
3.1. Chemistry
The synthetic routes of sulfonamide-derived 1,2,4-
triazoles were outlined in Scheme 1. During the procedure,
the N-protected sulfonyl chloride 2 was prepared with supe-
rior yield of 91% by the reaction of acetanilide with chloro-
sulfonic acid, and it was further treated by ammonium hy-
droxide to provide p-acetylaminobenzene sulfonamide 3 in
82% yield. Subsequent N-alkylation of compound 3 was
performed with a series of halobenzyl halides to afford the
secondary amine derivatives 4a–e with yields of 3%−17%.
Intermediates 4a–e further reacted with 1,2-dibromoethane
to obtain the tertiary amine sulfonamides 5a–e in good yields
of 70%–89%. Sulfonamide triazole intermediates 6a–e were
efficiently obtained by the N-alkylation of compounds 5a–e
with 1,2,4-triazole in 56%–78% yields.
2.1.30. Synthesis of N-(4-(N-(2-(1h-1,2,4-triazol-1-yl) ethyl)
Sulfamoyl) phenyl) acetamide (11)
Compound 11 was synthesized according to the experi-
mental procedure reported for compound 6a, starting from
compound 10 (0.420g, 1.0 mmol) and 1H-1, 2,4-triazole
(0.069 g, 1.0 mmol). The pure product 11 was obtained as
white solid. Yield: 82%; mp: 155–157ºC; IR (KBr) ν: 3303
(N−H), 3032 (aromatic C−H), 2995, 2924, 2875, 2812 (ali-
phatic C−H), 1687 (C=O), 1594, 1547, 1512 (aromatic
1
frame), 1323, 1161, 751, 579 cm-1; H NMR (600 MHz,
DMSO-d6) δ: 10.30 (s, 1H, NHCOCH3), 8.43 (s, 1H, TRA
C5-H), 7.94 (s, 1H, TRA C3-H), 7.75 (d, J = 8.5 Hz, 2H, Ph-
2,6-H), 7.71 (s, 1H, SO2NH), 7.69 (d, J = 8.5 Hz, 1H, Ph-
3,5-H), 4.22 (t, J = 6.1 Hz, 2H, NCH2CH2), 3.13 (t, J = 6.1
Hz, 2H, NCH2CH2), 2.09 (s, 3H, COCH3) ppm; 13C NMR
(151 MHz, DMSO-d6) δ: 169.4, 150.0 144.9, 143.4, 134.2,
128.1, 119.2, 49.0, 42.4, 24.6 ppm; HRMS (TOF) found, m/z
309.3447 [M + H]+, calcd for C12H12N5O3S: 309.3442.
To improve the yield of the target compounds, the second
synthetic route was designed by using t-butyloxy carbonyl
(Boc) group to protect one hydrogen atom of sulfonamide 3.
Thus the Boc-protected sulfonamide 8 and the by-product 9
were achieved from p-acetylaminobenzene sulfonamide 3 in
yields of 71% and 28%, respectively, and then compound 8
reacted with 1,2-dibromoethane to afford tert-N-sulfonamide
10 in yield of 64%. Subsequently, compound 10 experienced
nucleophilic substitution to conveniently afford the desired
sulfonamide intermediate 11 in a high yield of 82% and Boc
deprotected by-product 12 at a low yield of 18%. Further N-
alkylation of secondary amine 11 with halobenzyl halides
produced intermediates 6a–g with yields ranging from 67%
to 81%. Finally, intermediates 6a–g and 11 were further
transformed into the deprotected sulfonamide derivatives 7a-
2.1.31. Synthesis of tert-butyl (2-(1h-1,2,4-triazol-1-yl)
ethyl)((4-acetamidophenyl) sulfonyl) carbamate (12)
The by-product 12 was obtained as white solid from pro-
cedure for the preparation of compound 11. Yield: 18%; mp:
147–149ºC; IR (KBr) ν: 3432 (N−H), 3121, 3034 (aromatic
C−H), 299, 2935, 2803 (aliphatic C−H), 1728 (C=O), 1594,

Bioactivity Exploration of Sulfonamide-Derived Triazoles
Medicinal Chemistry, 2020, Vol. 16, No. 1 111
NH2
Br
O
S
NHCOCH3
NHCOCH3
S
O
O
O
HN
NHCOCH3
iv
i
ii
iii
N
S
NHCOCH3
R3
O
R1
R3
O
O
S
O
5a-e
R2
R1
R2
R1
NHCOCH3
vii
4a-e
R2
3
1
Cl
2
N
R3
NHCOCH3
vii
4-5:
N
N
a, R1 = Cl, R2 = H, R3 = H
b, R1 = H, R2 = H, R3 = F
c, R1 = H, R2 = H, R3 = Cl
d, R1 = Cl, R2 = H, R3 = Cl
e, R1 = H, R2 = Cl, R3 = Cl
v
N
O
S
O
S
O
H
Boc
7a-g
N
H3COCHN
R3
O
R2
vi
O
S
O
8
N
N
CH3
CH3
viii
Boc
R1
N
N
NH2
9
N
6-7:
H3C
N
a, R1 = H, R2 = H, R3 = H
b, R1 = F, R2 = H, R3 = H
c, R1 = Cl, R2 = H, R3 = H
d, R1 = H, R2 = H, R3 = F
e, R1 = H, R2 = H, R3 = Cl
f, R1 = Cl, R2 = H, R3 = Cl
N
N
Br
Boc
N
O
S
O
S
O
6a-g
H3COCHN
N
O
S
O
Boc
O
iii
12
v
O
g, R1 = H, R2 = Cl, R3 = Cl
N
N
NHCOCH3
O
vi
NH
11
S
H3COCHN
10
O
NHCOCH3
N
H2N
S
N
NH
N
O
N
13
Reagents and conditions: (i) chlorosulfonic acid, 0ºC; (ii) ammonium hydroxide, 0ºC; (iii) halobenzyl halide, potassium carbonate, acetone, 50−70ºC; (iv) 1,2-
dibromoethane, potassium carbonate, acetone, 50ºC; (v) 1,2,4-triazole, potassium carbonate, acetonitrile, 60−70ºC; (vi) 2 mol/L NaOH, ethanol, reflux; (vii)
di-tertbutyl dicarbonate, 4-(dimethylamino)-pyridine, triethylamine, dichloromethane, 0ºC−r.t.; (viii) 1,2-dibromoethane, potassium carbonate, acetonitrile,
60−70ºC.
Scheme 1. Synthesis of sulfonamide-derived 1,2,4-triazoles 4-13.
g and 13 in ethanol in order to explore their influence on the
but it exerted stronger anti-E. coli (DH52) activity (MIC =
0.04 μmol/mL) than Chloromycin. Among halobenzyl sul-
fonamide derivatives, sulfonamide 6d bearing 4-fluoro-
benzyl group showed better activities than compounds 6b
and 6e with 2-fluorobenzyl and 4-chlorobenzyl groups, how-
ever, it displayed relatively lower potencies in inhibiting the
growth of the tested strains than other substituted com-
pounds. The 2-chlorobenzyl compound 6c displayed equiva-
lent inhibitory potency to compounds 6f and 6g with di-
chlorobenzyl group against the tested strains. Especially,
replacement of 2-chlorobenzyl moiety with 2,4-dichloro-
benzyl group, which generated compound 6f, resulted in
good inhibitory potency against Gram-negative S. dysente-
riae with MIC value of 0.27 μmol/mL.
bioactivity.
3.2. Analysis of Spectra
1
For the IR, H NMR and 13C NMR spectra, all the ab-
sorption bands were observed at the expected regions. The
presence of acetylamino moiety of sulfonamide compounds
4−6 and 8−12 in IR spectra was confirmed by the broad ab-
sorption in 3394−3295 cm-1 for NH group and 1728−1670
cm-1 for characteristic C=O bands, whereas in 1H NMR spec-
tra, the CH3 protons linked to the amide moiety were ob-
served singlets at 2.07–2.12 ppm, and in 13C NMR spectra,
the carbonyl carbon was found at δ 169.7–168.7 ppm.
3.3. Biological Activity
Most of deprotected compounds 7a−g exerted relatively
superior activities in inhibiting the growth of the tested bac-
teria to the corresponding protected ones to some extent, and
compound 13 without halobenzyl group showed lower bio-
logical activities than halobenzyl contained ones.
The in vitro antibacterial and antifungal screening of the
sulfonamide compounds was explored normally [24]. The
antibacterial and antifungal data were displayed in Table 1
and Table 2.
Noticeably, the 1,2,4-triazole-based sulfonamide 7c bear-
ing 2-chlorobenzyl moiety showed the strongest inhibition
towards Gram-negative E. coli (DH52 and JM109) strains
(MIC= 0.02 μmol/mL), which was 5-fold more potent than
Chloromycin. Additionally, it displayed equivalent inhibi-
tory potency against MRSA to Chloromycin (MIC = 0.16
μmol/mL). This indicated that compound 7c could be further
studied as potential novel antibacterial agents. The
compounds 7b and 7c bearing chlorobenzyl moieties exerted
3.3.1. Antibacterial Activity
As shown in Table 1, the sulfonamides 5a−e exhibited
some activity against the tested bacterial strains with MIC
values ranging from 0.27 to 1.19 μmol/mL.
Some important effects of substituents on the benzene
ring on biological activity were observed. Non-substituted
derivative 6a possessed relatively weaker antibacterial activ-
ity in comparison with halogen substituted compounds 6b−g,

112 Medicinal Chemistry, 2020, Vol. 16, No. 1
He et al.
Table 1. Antibacterial data as MIC (μmol/mL) for compounds 5–13a,b, c
.
Gram-Positive Bacteria
Compds
Gram-Negative Bacteria
E. coli
E. coli
MRSA
S. aureus
B. subtilis
M. luteus
B. typhi
S. dysenteriae
(DH52)
(JM109)
5a
0.57
1.19
1.15
1.07
0.27
0.64
0.61
0.29
0.61
1.18
0.27
1.10
1.43
1.36
0.16
1.36
0.65
1.20
1.20
0.18
0.69
0.61
1.66
1.25
0.48
0.05
0.03
0.29
1.19
0.57
1.07
1.07
0.64
1.23
0.59
0.61
0.59
0.27
1.10
1.43
1.36
0.65
1.36
0.33
0.60
1.20
0.09
0.64
0.61
0.83
1.25
1.92
0.05
0.01
0.57
1.19
0.57
0.53
1.07
1.28
1.23
0.29
0.31
0.59
0.27
0.27
1.43
1.36
0.04
0.68
0.33
0.04
0.60
0.18
1.38
1.22
1.66
1.25
1.92
0.10
0.01
0.29
1.19
0.57
1.07
0.53
1.28
1.23
0.59
1.23
0.59
1.10
0.55
1.43
1.36
0.65
1.36
0.65
0.30
1.20
0.18
0.69
0.61
1.66
1.25
0.48
0.02
0.01
0.57
0.60
1.15
0.53
1.07
1.28
1.23
1.18
0.61
0.59
1.10
1.10
1.43
1.36
0.08
0.68
0.33
0.60
0.60
0.18
1.38
1.22
1.66
1.25
0.96
0.10
0.01
1.15
0.60
0.57
0.27
0.27
0.04
1.23
0.29
0.61
1.18
0.27
0.27
1.43
1.36
0.02
0.68
0.02
0.30
1.20
0.09
1.38
0.30
1.66
0.31
1.92
0.10
0.003
1.15
0.30
1.15
1.07
0.53
0.64
0.61
0.59
1.23
1.18
0.55
1.10
1.43
1.36
0.02
1.36
0.08
1.20
0.60
0.18
1.38
1.22
0.83
0.63
1.92
0.10
0.003
1.15
1.19
0.57
1.07
1.07
1.28
1.23
1.18
0.61
1.18
0.27
1.10
1.43
1.36
0.65
1.36
0.65
0.60
1.20
0.18
1.38
1.22
1.66
1.25
1.92
0.05
0.05
5b
5c
5d
5e
6a
6b
6c
6d
6e
6f
6g
7a
7b
7c
7d
7e
7f
7g
8
9
10
11
12
13
Chloromycin
Norfloxacin
aMinimal inhibitory concentrations were determined by micro broth dilution method for microdilution plates.
bS. aureus, Staphylococcus aureus (ATCC25923); MRSA, Methicillin-Resistant Staphylococcus aureus (N315); B. subtilis, Bacillus subtilis; M. luteus, Micrococcus luteus
(ATCC4698); B. proteus, Bacillus proteus (ATCC13315); E. coli, Escherichia coli (JM109); P. aeruginosa, Pseudomonas aeruginosa; B. typhi, Bacillus typhi.
cClogP values were calculated by ChemDraw Ultra 10.0.
Table 2. Antifungal data as MIC (μmol/mL) for compounds 5–13d.
Compds
5a
C. albicans
1.19
C. mycoderma
0.30
C. utilis
1.19
S. cerevisiae
1.19
A. flavus
1.19
5b
0.57
1.15
0.57
1.15
0.29
Table 2. contd…

Bioactivity Exploration of Sulfonamide-Derived Triazoles
Medicinal Chemistry, 2020, Vol. 16, No. 1 113
Compds
C. albicans
C. mycoderma
C. utilis
S. cerevisiae
A. flavus
5c
0.29
0.53
0.53
1.23
0.59
0.29
1.10
0.27
1.28
1.23
1.36
0.08
0.08
0.04
0.60
1.43
0.34
0.18
1.38
1.22
1.66
1.25
1.92
0.003
0.14
0.53
0.27
1.23
0.29
0.15
0.55
1.10
0.64
0.15
0.68
0.08
0.02
1.20
1.20
1.43
1.36
0.05
0.35
0.61
0.05
0.63
1.92
0.01
1.15
1.07
1.07
0.61
1.18
1.18
0.55
1.10
1.28
1.23
0.17
0.33
0.33
1.20
1.20
1.43
0.68
0.09
0.04
0.30
0.83
0.63
0.96
0.03
0.29
1.07
0.13
1.23
1.18
0.29
0.55
1.10
1.28
1.23
1.36
0.16
0.65
1.20
0.30
1.43
1.36
0.18
0.69
1.22
1.66
1.25
0.96
0.05
0.29
0.53
0.53
1.23
0.59
0.29
1.10
0.27
1.28
1.23
0.68
0.33
0.33
1.20
1.20
1.43
1.36
0.18
1.38
1.22
1.66
1.25
1.92
0.84
5d
5e
6a
6b
6c
6d
6e
6f
6g
7a
7b
7c
7d
7e
7f
7g
8
9
10
11
12
13
Fluconazole
dC. albicans, Candida albicans (ATCC76615); C. mycoderma, Candida mycoderma; C. utilis, Candida utilis; S. cerevisia, Saccharomyces cerevisia; A. flavus, Aspergillus flavus.
relatively better activity than the dichlorobenzyl group sub-
stituted ones 7f and 7g, which might probably be attributed
to change of the electronic distribution and physicochemical
properties, thereby affecting the absorption, distribution and
metabolism of the bioactive molecules. Moreover, sulfona-
mide 8 with Boc moiety exhibited high inhibitory activities
against S. aureus and E. coli DH52 strains with MIC values
of 0.09 μmol/mL. The deprotected sulfonamide triazole 11
displayed higher activity than the Boc-protected compound
12 to some extent. These results suggested that the Boc
group possessed remarkable effects on biological activities.
The good hydrophilicity of Boc moiety in these compounds
might make it easy for them be delivered to the binding sites.
ing from 0.27 to 1.19 μmol/mL, and notably compound 5e
with a 3,4-dichlorobenzyl group exhibited significant inhibi-
tory activity against S. cerevisiae with MIC value of 0.13
μmol/mL, which was equipotent to Fluconazole.
Among the halobenzyl sulfonamide 1,2,4-triazoles 6a−g
and 7a-g, compounds 6a and 7a without halogen atom
showed low activities in inhibiting the growth of all the
tested fungal strains. Moreover, 2-fluorobenzyl and 2-
chlorobenzyl substituted compounds 6b and 6c gave low
MIC value of 0.15 μmol/mL against C. mycoderma, which
was better than compound 6d with 4-fluorobenzyl group.
Intriguingly, 2-chlorobenzyl derivative 7c without acetyl
group exerted better anti-A. flavus activity (MIC = 0.33
μmol/mL) than Fluconazole (MIC = 0.84 μmol/mL), and it
also exhibited equivalent activity against C. mycoderma in
comparison with Fluconazole (MIC = 0.02 μmol/mL). Com-
pound 7d with 4-fluorobenzyl group showed better inhibi-
tory against C. utilis (MIC = 0.17 μmol/mL) than 2-
fluorobenzyl derivative 7b, whereas the latter exhibited bet-
ter activity against C. albicans than compound 7d. Sulfona-
3.3.2. Antifungal Activity
As depicted in Table 2, the in vitro antifungal data indi-
cated that some target sulfonamide-derived 1,2,4-triazoles
displayed moderate inhibitory potencies against the tested
fungal strains. Sulfonamide intermediates 5a−e showed
moderate to good antifungal activities with MIC values rang-

114 Medicinal Chemistry, 2020, Vol. 16, No. 1
He et al.
120
100
80
60
40
20
0
(MCF-7) by using the Cell-Counting Kit-8 (CCK-8) [25].
The phosphate buffered saline (PBS) was selected as a posi-
tive control (blank). Compound 7c was dissolved in a mix-
ture of ethanol and water to prepare the stock solutions,
which then was diluted by PBS to obtain the required con-
centrations of 6.25, 12.5, 25.0, 50.0 and 100.0 μg/mL, re-
spectively. The CKK-8 assay showed that compound 7c had
high cytotoxicity against MCF-7 with an IC50 value of 6.33
μg/mL Fig. (2). With the increase of the concentration of the
compound 7c, the cell viability decreased.
5. EVALUATION OF ROS GENERATION IN MCF-7
CELLS
6.25
12.5
25.0
50.0
100.0
Blank
Concentration (
ꢀ
g/mL)
Although the relationship between antimicrobial mecha-
nism and cell toxicity had not been fully elucidated [26], this
work studied the ROS level using DCFH-DA as a fluores-
cence probe and imaged by fluorescence microscope [27,
28]. To some extent, the amount of ROS produced in MCF-7
cells was positively correlated with anticancer activity.
However, excessive ROS might cause cellular injury and
thus lead to cell death and DNA damage. As shown in Fig.
(3), the generated amount of ROS increased with the increas-
ing concentration of compound 7c, thereby the anticancer
activity also increased. Especially, compound 7c showed
lower ROS generation than hydrogen peroxide (H2O2) at a
concentration of 100 μg/mL (safe dose to normal human
cells). Therefore, the newly synthesized compound 7c exhib-
ited better safety than the reference by downregulating ROS
generation.
Fig. (2). Cytotoxic assay of target compound 7c on human breast
cancer cell line (MCF-7) by CCK-8 Kit. Each data bar represents
an average of three parallels, and error bars indicate one standard
deviation from the mean (Blank: PBS). (A higher resolution / col-
our version of this figure is available in the electronic copy of the
article).
mide derivatives 7c and 7e−g with chlorine atom had rela-
tively better antifungal activity than fluorinated ones 7b and
7d, which indicated that the replacement of fluoro substitu-
ent with chloro moiety was beneficial for the antifungal ac-
tivity.
Compound 8 with a Boc moiety showed higher inhibitory
activity against Fluconazole-insensitive A. flavus with the
MIC value of 0.18 μmol/mL than Fluconazole (MIC = 0.84
μmol/mL). The t-butyl-derived by-product 9 exhibited excel-
lent inhibitory efficiency against C. utilis strains with MIC
value of 0.04 μmol/mL, which was superior to Fluconazole
(MIC = 0.03 μmol/mL). Sulfonamide 1,2,4-triazole 12
showed higher antifungal activity in comparison with the
corresponding Boc-deprotected one 11, which might be at-
tributed to the improved water solubility.
6. INTERACTIONS WITH CALF THYMUS DNA
Calf thymus deoxyribonucleic acid (DNA) was employed
to study the interaction behavior of compound 7c with it to
explore the possible antimicrobial mechanism [29, 30]. In
the experiments, the UV-vis spectra gave a proportional in-
crease and slight red shift with the increasing concentration
of compound 7c and a fixed concentration of DNA Fig. (4).
Besides, the sum value of free DNA and free compound 7c
was a little greater than the absorption value of 7c–DNA
complex (the inset of Fig. 4), which demonstrated that a
weak hypochromic effect is present between compound 7c
and DNA. The spectral changes might agree with the interca-
lation of compound 7c into the helix and the overlap of π-π*
states of DNA bases [31, 32]. The binding constant (K) was
As mentioned above, it was demonstrated that the antim-
icrobial efficacies might be closely related to acetyl frag-
ment, Boc moiety and different halobenzyl groups to some
extent.
4. CELL TOXICITY
The highly active compound 7c was further investigated
for its cytotoxic properties on human breast cancer cell lines
DMSO
100 μM H2O2
6.25 μM Compound 7c
12.5 μM Compound 7c
25 μM Compound 7c
50 μM Compound 7c
100 μM Compound 7c
Fig. (3). Compound 7c-induced ROS formation in MCF-7 cells and H2O2 as positive control. (A higher resolution / colour version of this
figure is available in the electronic copy of the article).

Bioactivity Exploration of Sulfonamide-Derived Triazoles
Medicinal Chemistry, 2020, Vol. 16, No. 1 115
1.0
0.8
7. MOLECULAR MODELING STUDIES
DNA-7c complex
0.7
DNA+ compound 7c
Docking study could offer more insights into understand-
ing the interactions of sulfonamide-derived 1,2,4-triazoles
and the structural features of the active site of protein. The
crystal structure data of human microsomal heme (PDB
code: 2HI4) was obtained from the Protein Data Bank
(PDB), which was a representative target to investigate the
antibacterial mechanism of 1,2,4-triazole derivatives. Target
compound 7c was selected to dock into the heme (the hemo-
globin complex Fe2+ of heme protein) to form a coordination
bond with the nitrogen atom in the 1,2,4-triazole ring, which
made the hemoglobin lose its chance of binding to oxygen
and inhibited the lanolin sterol 14α site demethylation reac-
tion, thereby the growth of the microorganism was inhibited
[33].
0.8
0.6
0.5
0.6
0.4
0.0
0.2
0.4
0.6
0.8
1.0
1.2
10-5 [Q] (mol/L)
0.4
0.2
0.0
DNA
225
250
275
300
325
350
Wavelength (nm)
Fig. (4). UV absorption spectra of DNA with different concentra-
tions of compound 7c (pH = 7.4, T = 293 K). Inset: comparison of
absorption at 260 nm between the 7c–DNA complex and the sum
values of free DNA and free compound 7c. c(DNA) = 4.85 × 10-5
mol/L, and c(compound 7c) = 0–1.17 × 10-5 mol/L for curves a–g
respectively at increment 0.167 × 10-5. (A higher resolution / colour
version of this figure is available in the electronic copy of the arti-
cle).
As shown in Fig. (6), it showed the detailed binding
mode between the active sites of human microsomal heme
and the most active derivative 7c bearing a 2-chlorobenzyl
group. The predominant intermolecular force of hydrogen
bond was labeled by a dashed line to understand the interac-
tion of the complex. The analyses of hydrogen bond interac-
tion confirmed that amino acid residue Ala 317 played a
relatively important role in binding potency. The backbone
of Ala 317 was inclined to form a hydrogen bond with one of
the oxygen atoms at -SO2NR in compound 7c, and the dis-
tance was 2.70 Å. The result demonstrated that compound 7c
could act with the heme protein through hydrogen bonds.
9
8
7
6
5
4
3
2
1
8. COMPUTATIONAL CHEMICAL STUDIES
In an attempt to understand the further possible mecha-
nism of the excellent biological activity and low toxicity of
active compound 7c bearing 2-chlorobenzyl groups, compu-
tational chemical assays were done and shown in Fig. (7).
Meanwhile, molecular electrostatic potential (MEP) and
atomic polar tensor (APT) charges had been performed to
explore the electrostatic binding characteristic through
the surface and atomic level of molecule, respectively
Fig. (7b-c). This MEP map was generated for a selection of
compound at the neutral state via the B3LYP/6-31C* theo-
retical computation [34, 35], and the MEP surface gave an
indication of the charged surface area and hydrophilicity of
compound (Fig. 7b). The results revealed that compound 7c
possessed more negative charge regions (in red) on the oxy-
gen and nitrogen atoms of -SO2NR than nitrogen atoms of
0
1
2
3
4
5
6
10-5[Q]-1 (mol/L)
Fig. (5). The plot of A0/(A-A0) versus 1/[compound 7c]. (A higher
resolution / colour version of this figure is available in the elec-
tronic copy of the article).
calculated using equation 1. The plot of A0/(A-A0) versus
1/[compound 7c] was obtained by using the absorption titra-
tion data and linear fitting Fig. (5), K = 1.14 × 104 L/mol, R
= 0.999, SD = 0.08 (R is the correlation coefficient. SD is
standard deviation).
ILE-386
PHE-125
ILE-117
LEU-497
THR-124
LEU-382
SER-123
THR-118
VAL-227
PHE-226
THR-498
PHE-256
THR-223
ASP-313
PHE-310
ASN-312
2.7
ALA-317
ALA-317
GLY-316
LEU-314
VAL-220
THR-321
ASP-320
GLY-318
PHE-319
PHE-315
(a)
(b)
(c)
Fig. (6). (a) Molecular modeling of compound 7c docked into the binding site of human microsomal heme (PDB: 2HI4). The dashed line
represent the hydrogen bonding interactions between compound 7c and heme; (b) Three-dimensional conformation of compound 7c docked
in heme; (c) Stereoview of the conformation of compound 7c intercalated to heme to form 7c–heme complex. (A higher resolution / colour
version of this figure is available in the electronic copy of the article).

116 Medicinal Chemistry, 2020, Vol. 16, No. 1
He et al.
-6.000 e-2
(0.049)
(0.247)
5 : (-0.517)
N
N
H2
(0.342)
N4 : (-0.276)
(0.069)
N3 : (-0.296)
(0.063)
(0.357)
O
S O
N
(-0.040)
(0.013)
(0.085)
(0.018)
O2 : (-0.855)
(0.304)
(-0.013)
(0.094)
N2
: (-0.997)
(-0.199)
(0.199)
(-0.036)
(0.366)
(-0.103)(0.386)
CI
N
N
(0.664)
1 : (2.279)
CI1 : (-0.340)
(-0.102)
S
N
(0.053)
(-0.430)
(0.091)
N1 : (-0.751)
(-0.196)
(0.198)
(0.045)
(-0.049)
O1: (-0.849)
(-0.003)
(-0.020)
(0.046)
(0.022)
Compound 7c
(0.017)
(0.014)
(0.077)
6.000 e-2
(a)
(b)
(c)
Fig. (7). (a) Structure of active compound 7c; (b) Electrostatic potential of compound 7c; (c) APT atomic charges of compound 7c. (A higher
resolution / colour version of this figure is available in the electronic copy of the article).
1,2,4-triazole ring (in yellow). The oxygen and nitrogen at-
oms of SO2NR were electronically available with their lone
pairs, which were probably oriented toward the outer part of
the molecule and therefore were accessible to interact with
their surroundings.
thymus DNA, which might be a factor to exert its powerful
bioactivity. Molecular docking indicated that compound 7c
could act with the residue of Ala 317 in human microsomal
heme protein through hydrogen bonds. The MEP surface and
APT atomic charges studies indicated the capability of hy-
drogen bond formation with one of the oxygen atoms in sul-
fonyl moiety, which were in agreement with the binding
mode obtained from the above docking study. All these re-
sults sufficiently indicated that it should be a promising start-
ing point to optimize the structures of sulfonamide-derived
1,2,4-triazoles as potential clinical antimicrobial candidates.
On the other hand, the APT atomic charges of compound
7c via the Gaussian 09 theoretical calculations were showed
in Fig. (7c). It was found that the APT charge of oxygen and
nitrogen atoms in -SO2NR moiety was lower than other at-
oms; especially the nitrogen atom had the lowest APT
charge. This data demonstrated that the oxygen and nitrogen
atoms in -SO2NR moiety were most likely to form hydrogen
bonds. Because of the π−π conjugative effect and steric hin-
drance, the nitrogen lone pairs in SO2NR moiety were buried
in the structure of compound 7c, which was favorable for
forming hydrogen bonds. It might indicate that the capability
of forming hydrogen bond was related with the nitrogen at-
oms of -SO2NR moiety. These results were in agreement
with the binding mode obtained from above docking study.
ETHICS APPROVAL AND CONSENT TO PARTICI-
PATE
Not applicable.
HUMAN AND ANIMAL RIGHTS
No Animals/Humans were used for studies that are the
basis of this research.
CONCLUSION
CONSENT FOR PUBLICATION
In this work, a series of sulfonamide–derived 1,2,4-
triazoles were successfully synthesized in two ways starting
from commercial commercial acetanilide and chlorosulfonic
acid. All the structures of the new compounds were charac-
Not applicable.
AVAILABILITY OF DATA AND MATERIALS
1
terized by IR, H NMR, 13C NMR and HRMS. The antimi-
The authors confirm that the data supporting the findings
of this study are available within the article and its supple-
mentary materials.
crobial evaluation in vitro revealed that some target com-
pounds showed effective antibacterial activity with suitable
ClogP values, and even displayed equipotent or superior
activities to the reference drugs. Structure-activity relation-
ships demonstrated that 1,2,4-triazole and sulfonyl fragments
exerted a significant influence on biological activity. No-
ticeably, 2-chlorobenzyl group substituted compound 7c
exhibited particularly strong antibacterial activity against
most of the tested bacterial and fungal strains (MIC = 0.02–
0.65 μmol/mL) and also displayed an objective cancer toxic-
ity against MCF-7 cells by evaluating cell toxicity and ROS
generation. The interaction of active compound 7c with calf
thymus DNA evidenced that it could properly bind with calf
FUNDING
This work was partially supported by the National Natu-
ral Science Foundation of China (No. 21672173), the Re-
search Fund for International Young Scientists from Interna-
tional (Regional) Cooperation and Exchange Program of
NSFC (No. 81650110529), Shandong Provincial Natural
Science Foundation (No. ZR2017PB001) and Doctoral Sci-
entific Research Foundation of Linyi University (No.
LYDX2016BS030).

Bioactivity Exploration of Sulfonamide-Derived Triazoles
Medicinal Chemistry, 2020, Vol. 16, No. 1 117
timicrobial evaluation of novel benzimidazole-incorporated sul-
fonamide analogues. Eur. J. Med. Chem., 2017, 136, 165-183.
[http://dx.doi.org/10.1016/j.ejmech.2017.04.077]
[PMID: 28494254]
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
otherwise.
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ACKNOWLEDGEMENTS
Declared none.
[http://dx.doi.org/10.1039/C4NJ01932F]
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SUPPLEMENTARY MATERIAL
Supplementary material is available on the publisher’s
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[http://dx.doi.org/10.1016/j.ejmech.2010.07.031]
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