Synthesis, characterization and biological activities of sulfonamide tagged 1,2,3-triazoles

Article abstract of DOI:10.1080/00397911.2020.1802758

The present paper elicits a marvelous synthesis of a series of sulfonamide containing 1,4-disubstituted 1,2,3-triazoles through click reaction of terminal alkynes with aromatic azides. The synthesized triazoles were characterized by FTIR, ¹H NM

Full text of DOI:10.1080/00397911.2020.1802758

Synthetic Communications
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Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Synthesis, characterization and biological activities
of sulfonamide tagged 1,2,3-triazoles
C. P. Kaushik , Manisha Chahal , Raj Luxmi , Devinder Kumar , Ashwani
Kumar , Mukesh Kumar & Dharmendra Singh
To cite this article: C. P. Kaushik , Manisha Chahal , Raj Luxmi , Devinder Kumar , Ashwani
Kumar , Mukesh Kumar & Dharmendra Singh (2020): Synthesis, characterization and
biological activities of sulfonamide tagged 1,2,3-triazoles, Synthetic Communications, DOI:
10.1080/00397911.2020.1802758
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SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2020.1802758
Synthesis, characterization and biological activities of
sulfonamide tagged 1,2,3-triazoles
C. P. Kaushika, Manisha Chahala, Raj Luxmia, Devinder Kumara, Ashwani Kumarb,
Mukesh Kumarc, and Dharmendra Singhd
aDepartment of Chemistry, Guru Jambheshwar University of Science and Technology, Hisar, India;
bDepartment of Pharmaceutical Sciences, Guru Jambheshwar University of Science and Technology,
c
Hisar, India; Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai,
d
India; Centre for Research and Development, IPCA Lab Ltd, Mumbai, India
ABSTRACT
ARTICLE HISTORY
Received 23 May 2020
The present paper elicits a marvelous synthesis of a series of sulfona-
mide containing 1,4-disubstituted 1,2,3-triazoles through click reac-
tion of terminal alkynes with aromatic azides. The synthesized
triazoles were characterized by FTIR, 1H NMR,13C NMR and HRMS
techniques. Further, the structures of synthesized compounds 6u
(CCDC 1954932) and 6z3 (CCDC 1954931) were also confirmed by X-
ray crystallography. The synthesized triazoles were evaluated for
in vitro antibacterial activity against S. aureus, B.subtilis, E. coli and K.
pneumoniae by serial dilution method. Among the series, compound
4-bromo-N-(2-(1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)propan-2-
yl)benzenesulfonamide, 6z4 (MIC ¼ 0.025 mM/mL) and 4-bromo-N-(2-
(1-(naphthalen-1-yl)-1H-1,2,3-triazol-4-yl)propan-2-yl)benzenesulfona-
mide 6z6 (MIC ¼ 0.027mM/mL) exhibited the appreciable antibacter-
ial activity against Staphylococcus aureus and Bacillus subtilis. Further,
the molecular docking studies of above potent analogs with dihy-
dropteroate synthase was performed to have an insight for binding
interactions. Synthesized molecules were also explored for antioxi-
dant activity, reflecting compound 6m as better radical scavenging
agent with IC50 value of 1.96 mM/mL.
KEYWORDS
Biological evaluation; click
chemistry; crystal structure;
sulfonamide; 123-triazole
GRAPHICAL ABSTRACT
CONTACT C. P. Kaushik
kaushikcp@gmail.com
Department of Chemistry, Guru Jambheshwar University of
Science and Technology, Hisar 125001, India.
ß 2020 Taylor & Francis Group, LLC

2
C. P. KAUSHIK ET AL.
Introduction
In the present scenario, the synthesis of newer heterocycles is the need of time to come
out with an effective pharmacophore with broad biological spectrum. In this sequence,
nitrogen containing heteroaromatics received considerable attention due to their wide bio-
logical applications. Among these, 1,2,3-triazoles are of key importance possessing varied
pharmaceutical applications in form of anticancer,[1–4] antimicrobial,[5–9] antiviral,[10,11]
antitubercular,[12–14] antioxidant,[15,16] anti-depressant,[17] anti-inflammatory,[18–20] anti-
malarial,[21,22] anti-protozoal,[23] anti-leishmanial,[24] anti-adipogenic,[25] Cholinesterase
inhibitory[26] agents. An effective and concrete synthesis of substituted 1,2,3-triazoles was
put forward by Sharpless[27,28] and coworkers, through click chemistry, involving cyclo-
addition reaction between terminal alkynes and azides using copper(I) as a catalyst yield-
ing 1,4-disubstituted isomer selectively. These copper(I) catalyzed synthesis are quiet
efficient, can be performed under mild reaction conditions and leads to interesting prod-
ucts having different functionalities/moieties with encouraging yields. Monocyclic 1,2,3-
triazoles are remarkably stable toward hydrolysis, oxidative/reductive conditions, and
enzymatic degradation. Some unique features like hydrogen bond formation, dipole-dipole
and p stacking interactions of triazoles have increased their significance in the field of
medicinal chemistry due to their effective binding with the biological targets. The triazole
also serves as synthetic intermediates in many industrial applications such as agrochemi-
cals,[29] corrosion inhibitors,[30,31] additives, dyes, polymer,[32,33] etc.
It has been stated that free radicals containing reactive oxygen species (ROS) like
superoxide (O2), hydroxyl (HO), peroxyl (ROO), alkoxyl (RO), and nitric oxide (NO)
radicals are highly reactive molecules and are believed to be associated with multiple
diseases conditions such as carcinogenesis, inflammation, mutagenesis, arthritis, cancer
and genotoxicity. In order to prevent the deleterious effects caused by free radicals in
the human body, there is need to cater the potential antioxidative agents in form of
newer molecules with broad biological significance.
Nowadays, antibiotic-resistant microbes are also making their inexorable march,
throwing a tough challenge to the organic chemists to synthesize more effective mole-
cules having an edge over existing drugs. Sulfonamides[34–36] were the first effective che-
motherapeutic agents to prevent and cure the bacterial infection in human beings as
early as 70 years ago.
Owing to the biological significance of sulfonamide moiety, it has been thought to
carry out synthesis of sulfonamide tagged 1,4-disubstituted 1,2,3-triazoles through
copper(I) catalyzed cycloaddition reaction between terminal alkynes and azides and to
evaluate the biological activity of synthesized triazoles in form of antibacterial (against
Staphylococcus aureus, Bacillus subtilis, Klebsiella pneumoniae, Escherichia coli) and anti-
oxidant agents.
Result and discussion
Chemistry
The work describes the synthesis of a series of sulfonamide tagged 1,4-disubstituted
1,2,3-triazoles (Scheme 1). In the first step, propargylation of commercially available

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SYNTHETIC COMMUNICATIONSV
3
Compounds
R1
R2
Reaction time
Yield (%)
(h)
4
6a
6b
6c
H
H
C6H5
82
82
78
84
85
75
82
82
78
76
86
72
82
86
84
84
85
78
83
76
72
78
88
68
88
81
91
68
85
64
82
82
4-CH3C6H4
4-NO2C6H4
4-FC6H4
5
H
5
6d
6e
H
7
H
4-ClC6H4
4-BrC6H4
m-pyridyl
α-naphthyl
C6H5
8
6f
H
6
6g
6h
6i
H
10
8
H
F
5
6j
F
4-CH3C6H4
4-NO2C6H4
4-FC6H4
6
6k
6l
F
6
F
5
6m
6n
6o
6p
6q
6r
F
4-ClC6H4
4-BrC6H4
m-pyridyl
α-naphthyl
C6H5
6
F
8
F
10
8
F
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
Br
Br
Br
5
4-CH3C6H4
4-NO2C6H4
4-FC6H4
4
6s
4
6t
6
6u
6v
6w
6x
6y
6z
4-ClC6H4
4-BrC6H4
m-pyridyl
α-naphthyl
C6H5
5
5
9
7
6
4-CH3C6H4
4-NO2C6H4
4-FC6H4
6
6z1
6z2
6z3
6z4
6z5
6z6
6
5
4-ClC6H4
4-BrC6H4
m-pyridyl
α-naphthyl
6
8
11
9
Scheme 1. Synthesis of sulfonamide containing 1,4-disubstituted 1,2,3-triazoles (6a–6z6).
aromatic sulfonyl chlorides[37,38] (1a–1d) was carried out by 1,1-dimethylpropargyl-
amine (2) in the presence of 4-(dimethylamino)pyridine (DMAP) in dichloromethane.
The aromatic azides (5a–5h) were synthesized from aromatic amines by dropwise add-
ition of dilute HCl and NaNO2 followed by the addition of sodium azide in

4
C. P. KAUSHIK ET AL.
1
Figure 1. Chemical shift (d) values of H NMR of compound 6u.
dichloromethane. After this, the terminal alkynes (3a–3d) were subjected to the reaction
with aromatic azides (5a–5h), in the presence of catalytic amount of copper sulfate pen-
tahydrate and sodium ascorbate in DMF: H2O (8:2) to furnish desired triazoles (6a–6z6)
in good yields.
The structure of all the synthesized triazoles was established on the basis of various
1
analytical techniques i.e., FTIR, H and 13C NMR, HRMS. The FTIR spectra of the syn-
thesized triazoles (6a–6z6) displayed characteristic absorption bands in the regions at
3118–3308 and 3007–3153 cmꢀ1 due to the N–H and C–H stretching vibrations of tri-
azole ring, respectively. The S¼O asymmetric and symmetric stretching bands of sul-
fonamide were observed in the regions 1311–1342 and 1143–1161 cmꢀ1 respectively.
1
The H NMR spectra of all the compounds, exhibited characteristic singlet due to tria-
zolyl proton in the region d 7.79–8.68 and the singlet due to N–H proton appeared at d
8.33–8.99. A singlet in the region of d 1.60–1.69 was assigned to the six protons of two
aliphatic methyl groups. Moreover, in 13C NMR spectra, the appearance of signals in
the region of d 141.0–143.0 and d 119.8–121.0 assigned to C4 and C5 of triazole ring
confirmed the formation of target compounds. Further, the results obtained from high-
resolution mass spectrometry (HRMS) were found in accordance with theoretically pre-
dicted molecular masses. The structure of compound 6u and 6z3 was further confirmed
by X-ray crystallography.
To have a better clarity between two aromatic rings present in the synthesized mol-
ecule it has been thought to utilize 2 D-NMR spectroscopy (COSY, TOCSY, HSQC and
HMBC). The structure of representative molecule 6u was further confirmed by X-ray
crystallography study.
FTIR spectrum of 6u displayed absorption at 3142 (N–H str.), 3086 (C–H str., tri-
azole ring), 2985 (C–H str., aliphatic), 1546, 1454 (C¼C str., aromatic ring), 1323 (S¼O
1
asym. str., sulfonamide), 1143 (S¼O sym. str., sulfonamide) cm ꢀ1. H NMR spectrum
of 6u (Figure 1) exhibited one proton singlet in the most downfield region centered at
d 8.44 was expediently assigned to N–H and another one proton singlet at d 8.25 due
to C5–H. Four doublets at 7.79, 7.66, 7.50, 7.34 each integrating for two protons were
assigned to C2’, C3’, C2’’ and C3’’ respectively and another singlet at d 1.64 due to six

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Figure 2. Chemical shift (d) values of 13C NMR of compound 6u.
protons of –C(CH3)2. The 13C NMR spectrum of 6u (Figure 2) exhibited a signal in the
most downfield region at d 151.87 ppm, which was safely attributed to C4 of the triazole
ring. The peak in the most shielded region at 29.10 ppm was assigned to –C(CH3)2 and
another peak at 52.99 ppm was attributed to the –C(CH3)2. 135-DEPT spectrum of
compound 6u confirmed the presence five carbon signal of methine and one carbon
signal of methyl carbon. These assignments were further confirmed by 2 D NMR spec-
1
1
1
tral studies i.e., H–1H COSY, TOCSY, H –13C HSQC and HMBC. The H–1H correla-
tions between d 7.79 (C2’–H) and 7.66 (C3’–H); d 7.50 (C2’’–H) and d 7.34 (C3’’–H)
were established through COSY spectrum. The HSQC experiments revealed the assign-
ment of carbon signals at 121.80 (C2’), 130.22 (C3’), 128.72 (C2’’), 128.90 (C3’’), 120.96
(C5), 29.10 [–C(CH3)2] because the key correlation (1H–13C) was observed as: d 7.79
(C2’–H)/dC 121.80 (C2’); dH 7.66 (C3’–H)/dC 130.22 (C3’), dH 7.50 (C2’’–H)/dC 128.72
(C2’’), dH 7.34 (C3’’–H)/dC 128.90 (C3’’), dH 8.25 (C5–H)/dC 120.96 (C5) and dH 1.64
–C(CH3)2/dC 29.10. Heteronuclear Multiple Bond Correlation (HMBC) experiment
reflected the linkage involving hydrogen with other carbons through multiple bond cor-
relation of signals at d 1.64–29.1, 52.9, 151.8 (C4); d 8.24–29.1, 52.9, 151.8; d 7.50–136.9,
128.72, 141.6 (C1’’); d 7.34–136.9, 128.72, 141.6 (C1’’). Additionally, HMBC and 135-
DEPT spectra of 6u proved helpful toward chemical shift assignments of proton and
carbon signals. Further HRMS analysis result of 6u was found in full agreement with its
molecular weight (vide experimental).
X-ray crystallographic study
Single crystals of 4-chloro-N-(2-(1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)propan-2-
yl)benzenesulfonamide (6u) (Table 1; Figure 3) and 4-bromo-N-(2-(1-(4-chlorophenyl)-
1H-1,2,3-triazol-4-yl)propan-2-yl)benzenesulfonamide (6z3) (Table 2; Figure 4) were
grown in ethyl acetate and methanol (3:1) using the slow evaporation technique. Single
crystal data for compounds 6u and 6z3 was deposited in the Cambridge
Crystallographic Data Center and assigned to the CCDC 1954932 and CCDC 1954931,
respectively, which is available online at www.ccdc.cam.ac.uk/conts/retrieving.html.

6
C. P. KAUSHIK ET AL.
Table 1. Crystal data and structure refinement for 4-chloro-N-(2-(1-
(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)propan-2-yl)benzenesulfona-
mide (6u).
Property
Data
Empirical formula
Formula weight
Temperature/K
Crystal system
Space group
C17H16N4O2SCl2
411.30
293
Monoclinic
P21/c
a/Å
9.6248(4)
b/Å
10.5238(5)
18.3928(10)
90, 91.214(5), 90
1862.59(16)
4
c/Å
a/ꢁ, b/ꢁ, c/ꢁ
Volume/Å3
Z
qcalcg/cm3
1.467
4.357
m/mmꢀ1
F(000)
848.0
Crystal size/mm3
Radiation
0.81 ꢂ 0.75 ꢂ 0.229
CuKa (k ¼ 1.54184)
9.19 to 146.374
2H range for data collection/ꢁ
Index ranges
ꢀ11 ꢃ h ꢃ 9, ꢀ8 ꢃ k ꢃ 12, ꢀ20 ꢃ l ꢃ 22
Reflections collected
Independent reflections
Data/restraints/parameters
Goodness-of-fit on F2
Final R indexes [I > ¼ 2r (I)]
Final R indexes [all data]
6953
3605 [Rint ¼ 0.0966, Rsigma ¼ 0.0939]
3605/0/238
1.265
R1 ¼ 0.1094, wR2 ¼ 0.2827
R1 ¼ 0.1310, wR2 ¼ 0.3369
Figure 3. Crystal structure of 4-chloro-N-(2-(1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)propan-2-yl)benze-
nesulfonamide (6u) [CCDC 1954932].

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Table 2. Crystal data and structure refinement for 4-bromo-N-(2-(1-(4-chlor-
ophenyl)-1H-1,2,3-triazol-4-yl)propan-2-yl)benzenesulfonamide (6z3).
Property
Data
Empirical formula
Formula weight
Temperature/K
Crystal system
Space group
C17H16N4O2SClBr
455.76
293
Monoclinic
P21/n
a/Å
b/Å
20.8494(13)
10.4818(4)
9.7097(5)
90, 117.828(7), 90
1876.5(2)
c/Å
a/ꢁ b/ꢁ c/ꢁ
Volume/Å3
Z
4
qcalcg/cm3
1.613
5.510
l/mm-1
F(000)
920.0
Crystal size/mm3
Radiation
0.98 ꢂ 0.677 ꢂ 0.221
CuKa (k ¼ 1.54184)
9.108 to 146.598
2H range for data collection/ꢁ
Index ranges
ꢀ25 ꢃ h ꢃ 23, ꢀ12 ꢃ k ꢃ 12, ꢀ11 ꢃ l ꢃ 12
Reflections collected
Independent reflections
Data/restraints/parameters
Goodness-of-fit on F2
Final R indexes [I > ¼ 2r (I)]
Final R indexes [all data]
Largest diff. peak/hole / e Åꢀ3
10,734
3672 [Rint ¼ 0.1103, Rsigma ¼ 0.0743]
3672/0/238
1.358
R1 ¼ 0.1154, wR2 ¼ 0.3046
R1 ¼ 0.1375, wR2 ¼ 0.3513
1.78/ꢀ1.15
Figure 4. Crystal structure of 4-bromo-N-(2-(1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)propan-2-yl)benze-
nesulfonamide (6z3) [CCDC 1954931].

8
C. P. KAUSHIK ET AL.
Figure 5. In vitro antibacterial activity of the synthesized compounds (6a–6z6) in terms of Minimum
inhibitory concentration (MIC) (mmol/mL).
Antibacterial activity
All the synthesized compounds were assessed for in vitro antibacterial activity against S.
aureus, B. subtilis, K. pneumoniae, E. coli. Antibacterial activities of synthesized com-
pounds were evaluated by following the procedure reported by Kaushik et al.[39]
Minimum Inhibitory Concentration (MIC) is reflected in mmol/mL as presented in
Figure 5 and Table 3. Ciprofloxacin was used as a standard drug.
Among the synthesized series, the compounds 6j (MIC 0.033), 6z (MIC 0.028), 6z1
(MIC 0.025), 6z4 (MIC 0.025), 6z6 (MIC 0.027 mM/mL) against S. aureus, compounds
6z (MIC 0.028), 6z4 (MIC 0.025) and 6z6 (MIC 0.027) against B. subtilis, compounds 6f
(MIC 0.029) and 6z5 (MIC 0.029) against K. pneumoniae, compounds 6p (MIC 0.030)
and 6v (MIC 0.027) against E. coli. exhibited significant antibacterial activity in com-
parison to reference drug.
It has been observed that the antibacterial is quite influenced by the nature of the substitu-
ent present on triazole ring. The antibacterial data in Table 3 showed that all the tested com-
pounds exhibited a marked degree of activity against all the tested bacterial strain compared
with standard drug. Structure with relation to biological activity reflected that substitution of
aromatic ring hydrogen attached to nitrogen of triazole ring increases the antibacterial activ-
ity in most of the cases. The presence of bromo group on the aromatic ring attached to the
nitrogen of triazole showed enhanced activity in comparison to F and Cl. The presence of
nitro group on the aromatic ring attached to the N of triazole showed improved activity in

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9
Table 3. In vitro antibacterial activity of compounds 6a–6z6 (MIC in mmol/mL).
Staphylococcus aureus
(MTCC 7443)
Bacillus subtilis
(MTCC 441)
Klebsiella pneumoniae
Escherichia
coli (MTCC1231)
Compounds
(NCDC 138)
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
6s
6t
6u
6v
6w
6x
6y
6z
6z1
6z2
6z3
6z4
6z5
6z6
0.073
0.070
0.064
0.069
0.066
0.059
0.073
0.064
0.069
0.033
0.061
0.066
0.063
0.114
0.069
0.060
0.132
0.063
0.059
0.063
0.121
0.110
0.066
0.058
0.059
0.028
0.025
0.057
0.055
0.025
0.059
0.027
0.019
0.073
0.070
0.064
0.069
0.066
0.059
0.072
0.063
0.069
0.066
0.123
0.132
0.063
0.057
0.138
0.121
0.066
0.127
0.059
0.063
0.060
0.055
0.132
0.058
0.059
0.055
0.053
0.057
0.055
0.025
0.059
0.027
0.019
0.073
0.067
0.064
0.069
0.066
0.029
0.072
0.063
0.138
0.138
0.123
0.132
0.253
0.228
0.069
0.243
0.265
0.127
0.118
0.126
0.121
0.110
0.132
0.117
0.059
0.055
0.053
0.114
0.220
0.100
0.029
0.053
0.019
0.073
0.067
0.064
0.138
0.066
0.059
0.072
0.063
0.069
0.069
0.061
0.132
0.126
0.114
0.069
0.030
0.066
0.061
0.059
0.063
0.060
0.027
0.066
0.058
0.059
0.111
0.107
0.057
0.055
0.050
0.118
0.053
0.019
Ciprofloxacin
comparison to methyl group i.e., electron donating group showed better activity than elec-
tron withdrawing group. Replacement of phenyl ring attached to nitrogen of triazole with
naphthyl ring also increases the activity of the compounds. Also, substituent on phenyl ring
attached to sulfonamide group enhanced antibacterial potential. Bromo group on aromatic
ring attached to nitrogen of sulfonamide showed better antibacterial activity than their halo
counterparts.
Antioxidant activity
The in vitro antioxidant activity of synthesized compounds was performed spectrophoto-
metrically using 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assay with as
standard by following the procedure reported by Shaikh et al.[40] DPPH radical scavenging
procedure is a rapid and convenient assay for screening the antioxidant activities of prod-
ucts. Figure 6 and Table 4 summarize the radical scavenging activities of all compounds,
compared to the synthetic antioxidant. Compound 6p was found to be most active with IC50
value of 1.96 mM/mL. Compounds 6i, 6k, 6l, 6n also showed good radical scavenging activ-
ity with IC50 value of 2.44, 2.42, 2.40, 2.64mM/mL respectively.
Compounds containing naphthyl ring were found to exhibit diligent activity as com-
pared to phenyl ring attached to nitrogen of triazole. Triazoles having nitro substituent

10
C. P. KAUSHIK ET AL.
8
7
6
5
4
3
2
1
0
Compounds
Figure 6. In vitro antioxidant activity of compounds 6a–6z6 (IC50 value in mmol/mL).
Table 4. In vitro antioxidant activity of compounds 6a–6z6 (IC50 value in mmol/mL).
Compound
IC50
Compound
IC50
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6.9
6r
6s
6t
6u
6v
6w
6x
6y
6z
6z1
6z2
6z3
6z4
6z5
6z6
7.25
3.57
6.37
5.89
5.42
3.52
3.98
4.75
5.08
4.12
5.81
6.53
4.47
3.97
4.49
1.23
4.98
3.71
4.19
4.29
5.37
5.66
4.31
2.44
2.98
2.42
2.4
1.92
2.64
3.59
2.82
4.71
Ascorbic acid
have better inhibition as compared to methyl substituted triazoles. In case of scaffolds
carrying halogens, those with fluoro substituent are more active than chloro and bromo
congeners. Pyridyl derivatives showed enhanced activity as compared to phenyl group
containing triazoles in most of the cases. Overall data suggested that to achieve antioxi-
dant activity against DPPH the nature of substituent on the phenyl ring was important.
Docking studies
Antibiotics containing sulfonamide moiety inhibits dihydropteroate synthase (DHPS)
which is an important enzyme in folate pathway in bacteria. These drugs compete
with p-aminobenzoic acid for condensation with 6-hydroxymethyl-7,8–dihydropterin-
pyrophosphate. Keeping these facts in view, compounds 6z4 and 6z6 with better anti-
microbial activity were docked in active site of enzyme DHPS. The docked compounds
along with interacting residues are shown in Figures 7 and 8. Figure 9 shows binding

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11
Figure 7. Interactions of compound 6z4 with active site residues of DHPS.
Figure 8. Interactions of compound 6z6 with active site residues of DHPS.
interactions of co-crystallized sulfamethoxazole. One oxygen atom of sulfonamide moiety
of compound 6z4 created hydrogen bonds with Ser222 and Arg235. Bromine atom made
a carbon hydrogen bond with Lys221. Bromophenyl ring attached with sulfur was
involved in T-shaped pi-pi stacking interactions with Phe28. Pro64 and Phe190 were
involved in hydrophobic interactions with 6z4. Compound 6z6 also interacted with the
same residues but hydrogen bond with Ser222 was absent in this case which is crucial for
binding of p-aminobenzoic acid as well as sulfonamide drugs. The binding affinity of
these compounds was ꢀ6.8 kcal/mol and ꢀ6.6 kcal/mol respectively, which are also in
correlation with their activity against Staphylococcus aureus, Bacillus subtilis, and
Escherichia coli. Docked confirmation of these two compounds along with sulfamethoxa-
zole is exhibited in cartoon diagram in Figure 10. 2 D depiction of interactions of com-
pound (a) 6z4 (b) 6z6 and (c) sulfamethoxazole (SMX) with active site residues of DHPS
shown in Figure 11. Detailed interactions of docked compounds are given in Table 5.

12
C. P. KAUSHIK ET AL.
Figure 9. Interactions of sulfamethoxazoe with active site residues of DHPS.
Figure 10. Docked conformation of compounds 6z4 and 6z6 along with co-crystallized sulfamethoxa-
zole in DHPS.

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SYNTHETIC COMMUNICATIONSV
13
Figure 11. 2 D depiction of interactions of compound (a) 6z4 (b) 6z6 and (c) sulfamethoxazole (SMX)
with active site residues of DHPS.
Experimental
General information
The starting materials were purchased from Sigma-Aldrich, Alfa-Aesar, Hi-Media and used
without any further purification. Melting points (ꢁC) were determined by open capillaries
and are uncorrected. Analytical Thin-layer chromatography (TLC) was performed using

14
C. P. KAUSHIK ET AL.
Table 5. Details of interactions of docked compounds.
Compound
Residue
Category of interaction
Type of interaction
Distance
6z4
SER222
ARG235
LYS221
SER222
PHE28
PRO64
LYS221
PRO64
LYS221
PRO64
PHE190
Hydrogen Bond
Hydrogen Bond
Hydrogen Bond
Hydrogen Bond
Hydrophobic
Hydrophobic
Hydrophobic
Hydrophobic
Hydrophobic
Hydrophobic
Hydrophobic
Conventional Hydrogen Bond
Conventional Hydrogen Bond
Carbon Hydrogen Bond
Carbon Hydrogen Bond
Pi-Pi T-shaped
Alkyl
Alkyl
Pi-Alkyl
Pi-Alkyl
Pi-Alkyl
2.90782
2.24872
3.66251
3.22237
4.80826
5.32876
4.89105
4.60217
4.55286
4.35504
3.6359
Pi-Alkyl
6z6
ARG235
LYS221
SER222
PHE28
PRO64
LYS221
PRO64
PRO64
LYS221
PRO64
PHE190
Hydrogen Bond
Hydrogen Bond
Hydrogen Bond
Hydrophobic
Hydrophobic
Hydrophobic
Hydrophobic
Hydrophobic
Hydrophobic
Hydrophobic
Hydrophobic
Conventional Hydrogen Bond
1.96964
3.70799
3.08307
4.75137
5.1749
4.81249
4.90514
4.69767
4.55152
5.01427
3.88686
Carbon Hydrogen Bond
Carbon Hydrogen Bond
Pi-Pi T-shaped
Alkyl
Alkyl
Pi-Alkyl
Pi-Alkyl
Pi-Alkyl
Pi-Alkyl
Pi-Alkyl
SMX
HH2278
THR62
SER222
PHE28
PHE190
ARG63
PRO64
LYS221
ARG63
PRO64
Hydrogen Bond
Hydrogen Bond
Hydrogen Bond
Hydrophobic
Hydrophobic
Hydrophobic
Hydrophobic
Hydrophobic
Hydrophobic
Hydrophobic
Conventional Hydrogen Bond
Conventional Hydrogen Bond
Conventional Hydrogen Bond
Pi-Pi T-shaped
Pi-Pi T-shaped
Pi-Alkyl
Pi-Alkyl
Pi-Alkyl
Pi-Alkyl
Pi-Alkyl
2.10511
2.7681
1.98315
5.01272
5.13468
5.14762
4.94372
4.84487
5.33765
3.78151
silica gel plates (SIL G/UV254, ALUGRAM) to monitor the progress of reaction and to
check the purity of compounds. The IR spectra were taken on SHIMAZDU IR AFFINITY-I
FTIR spectrometer using potassium bromide (KBr) powder and values are given in cmꢀ1.
Nuclear magnetic resonance (NMR) spectra were recorded on BRUKER AVANCE II instru-
ment operating at 400 MHz (1H) and 100 MHz (13C), in DMSO, and chemical shifts (d) are
recorded in parts per million downfield from the internal standard trimethylsilane (TMS).
Coupling constant (J) values were observed in Hertz (Hz). HRMS were observed on Bruker
micro TOF Q-II spectrometer.
Procedure for synthesis of N-(2-(1-phenyl-1H-1,2,3-triazol-4-yl)propan-2-
yl)benzenesulfonamide (6a)
N-(2-methylbut-3-yn-2-yl)benzenesulfonamide (3a) was synthesized by dropwise add-
ition of 1,1-dimethylpropargyl amine (2) (1.0 mmol) to the stirred solution of benzene-
sulfonylchlorides (1.0 mmol) (1a) in dichloromethane in presence of 4-
(dimethylamino)pyridine (DMAP) as base at 0–10 ꢁC for 2–3 h.

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SYNTHETIC COMMUNICATIONSV
15
Azidobenzene (5a) was synthesized by reaction of aniline (4a) (1.0 mmol) and
dilute HCl, saturated solution of sodium nitrite was added dropwise at 0–5 ꢁC. Stirred
the content for 30 minutes, then aqueous solution of sodium azide (3.0 mmol) was
added to the reaction mixture at 0–5 ꢁC and stirred further for 2–3 h at same
temperature.
Finally, N-(2-(1-phenyl-1H-1,2,3-triazol-4-yl)propan-2-yl)benzenesulfonamide (6a)
was synthesized from reaction of N-(2-methylbut-3-yn-2-yl)benzenesulfonamide (3a)
(1.0 mmol) and Azidobenzene (5a) (1.0 mmol) using dimethylformamide:water (8:2)
as solvent in the presence of copper sulfate pentahydrate (0.2 mmol) and sodium
ascorbate (0.4 mmol) with continuous stirring at 40 ꢁC for 4 h. Progress of the reac-
tion was monitored by TLC, after completion of reaction, reaction mixture was
quenched with ice-cold water and ammonia solution, product was extracted with
ethyl acetate to get white solid product in 82% yield, mp: 152–156 ꢁC; FTIR (KBr):
ꢀmax ¼ 3207 (N–H str.), 3026 (C–H str., triazole ring), 2881 (C–H str., aliphatic),
1504, 1456 (C¼C str., aromatic ring), 1327 (S¼O asym. str., sulfonamide), 1149
1
(S¼O sym. str., sulfonamide) cmꢀ1; H NMR (400 MHz, DMSO-d6) d 8.41 (s, 1H,
–NH), 8.12 (s, 1H, C-H triazole), 7.74 (d, J ¼ 8.0 Hz, 2H), 7.59–7.55 (m, 4H), 7.47
(t, J ¼ 8.0 Hz, 1H), 7.39–7.31 (m, 3H), 1.62 (s, 6H); 13C NMR (100 MHz, DMSO-d6)
d 152.35 (C4 triazole), 143.18, 137.01, 132.01, 130.22, 128.87, 126.74, 120.80 (C5 tri-
azole), 120.39, 53.07, 29.20; HRMS (m/z) calculated for C17H18N4O2S [M þ H]þ:
343.1150. Found: 343.1086.
X-ray crystallographic study
Single crystals of C17H16N4O2SClBr (6u) and C17H16N4O2SCl2 (6z3) was selected and
determined on a SuperNova, Single source at offset, Titan diffractometer. The crystal
was kept at 293 K during data collection. Using Olex2,[41] the structure was solved with
the ShelXT[42] structure solution program using Direct Methods and refined with the
ShelXL refinement package using Least Squares minimization.
General procedure for in vitro antibacterial evaluation
Two Gram-positive bacterial strains: S. aureus (MTCC 3160), B. subtilis (MTCC 441)
and two Gram-negative bacterial strain: E. coli (MTCC 443), K. pneumoniae (NCDC
138) were used for in vitro antibacterial screening of synthesized triazole derivatives by
serial dilution technique.[43,44] To get the stock solution of 200 mg/mL concentration,
2.0 mg of synthesized compound was dissolved in 10 mL of DMSO. Fresh nutrient broth
was used as a culture media for bacterial strains. Initially, 1 mL of nutrient broth was
taken in each test tube and 1 mL of stock solution was added in one test tube to get the
solution of 100 mg/mL concentration. Further, the concentration of 50–3.12 mg/ml were
also obtained through serial dilution technique. After that, 0.1 mL of respective micro-
organism in sterile saline was inoculated in each test tube and then incubated at 37 ꢁC
for 24 h.

16
C. P. KAUSHIK ET AL.
General procedure for in vitro antioxidant activity
The in vitro antioxidant activity of synthesized compounds was performed spectro-
photometrically using 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging
assay.[45] Stock solutions of the compounds (100 mg/mL) were prepared in methanol
and diluted to different concentrations in the range of 20–100 mg/mL in methanol.
Methanol, DPPH solution and standard drugs were used as blank, control and reference
respectively. Solution of organic compounds were taken in test tubes (2 mL) and then
freshly prepared DPPH solution (1 mL) (0.004 g DPPH in 100 mL methanol) was added
to every test tube. The samples were kept in the dark for 30 min after which absorbance
was read against a blank at 517 nm (at an absorption maximum of DPPH) with UV-
Visible spectrophotometer and the percentage of scavenging activity was calculated. The
percentage of radical scavenging activity (RSA %) (I %) of the tested compounds was
calculated according to the following equation:
RSA % ¼ ðA0 ꢀ A1Þ=A0 ꢂ 100
where A0 is the absorbance of the control reaction and A1 is the absorbance of the
test sample.
Docking
The desired protein dihydropteroate synthase (PDB ID: 3TZF) was taken from protein
data bank[46] as this protein is complexed with known sulfonamide drug sulfamethoxa-
zole and protein preparation was performed using Chimera tool.[47] The structures of
small compounds were prepared and optimized with MarvinSketch[48] and results were
visualized with Discovery studio[49] and PyMOL.[50] Docking studies were carried out
with Autodock Vina program[51] and the docking protocols were validated by redocking
ꢀ
of the co-crystallized ligand SMX which resulted into the conformation within 2Å
RMSD of the co-crystallized conformation. These docking protocols with search box of
dimensions center_x ¼ 28.923181887, center_y
¼
ꢀ1.2838, center_z ¼ 9.0701,
size_x ¼ 20.0934362261, size_y ¼ 25.0, size_z ¼ 25.0 were used for final study.
Conclusion
In precise, we have reported a series of composite scaffold having sulfonamide tagged
1,4-disubstituted 1,2,3-triazoles obtained through Cu(I)-catalyzed click reaction of aro-
matic azides and sulfonamide containing alkynes. All the synthesized 1,2,3-triazoles
were characterized by analytical techniques—IR, 1H NMR, 13C NMR and HRMS.
Further, structures of compounds 6u (CCDC 1954932) and 6z3 (CCDC 1954931) were
also confirmed by X-ray crystallography. Antibacterial activity of all the synthesized tria-
zoles has been evaluated against four bacterial strains reflected moderate to good effi-
cacy, however, the compound 6z4 (MIC ¼ 0.025 mM/mL) exhibited appreciable
antibacterial activity against B. subtilis and S. aureus. Molecular docking investigation
for the broadly active compound was in parallel to the in vitro antibacterial potency
results. Further, the synthesized molecules were also examined for antioxidant activity,

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SYNTHETIC COMMUNICATIONSV
17
in which compound 6m (IC50 ¼ 1.96 mM/mL) revealed best radical scavenging activity
among the synthesized triazoles.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Funding
Authors are highly thankful to the Council of Scientific and Industrial Research (CSIR) for finan-
cial assistance.
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