Facile synthesis, characterization, and antimicrobial studies of some disubstituted 1,2,3-triazoles with sulfonamide functionality

Article abstract of DOI:10.1080/00397911.2017.1333124

An expedient synthesis of some 1,4-disubstituted 1,2,3-triazoles (3a–3x) having sulfonamide functionality from various terminal alkynes and aromatic azides through Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition has been reported. The structures of newl

Full text of DOI:10.1080/00397911.2017.1333124

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Facile Synthesis, Characterization and
Antimicrobial Studies of Some Disubstituted 1,2,3-
triazoles with Sulfonamide Functionality
C. P. Kaushik, Ashima Pahwa, Ashwani Kumar, Dharmendra Singh & Krishan
Kumar
To cite this article: C. P. Kaushik, Ashima Pahwa, Ashwani Kumar, Dharmendra Singh &
Krishan Kumar (2017): Facile Synthesis, Characterization and Antimicrobial Studies of Some
Disubstituted 1,2,3-triazoles with Sulfonamide Functionality, Synthetic Communications, DOI:
10.1080/00397911.2017.1333124
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1333124
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Date: 26 May 2017, At: 22:40

Facile Synthesis, Characterization and Antimicrobial Studies of Some Disubstituted
1,2,3-Triazoles with Sulfonamide Functionality
C. P. Kaushik1, Ashima Pahwa1, Ashwani Kumar2, Dharmendra Singh3, Krishan Kumar1
1Department of Chemistry, Guru Jambheshwar University of Science & Technology,
Hisar, Haryana, India 2Department of Pharmaceutical Sciences, Guru Jambheshwar
University of Science &Technology, Hisar, Haryana, India 3Centre for Research &
Development, IPCA Lab Ltd., Kandivali, Mumbai, Maharashtra, India
Corresponding author C.P. Kaushik E-mail: kaushikcp@gmail.com
Abstract
An expedient synthesis of some 1,4-disubstituted 1,2,3-triazoles (3a–3x) having
sulfonamide functionality from various terminal alkynes and aromatic azides via Cu(I)
catalyzed Huisgen 1,3-dipolar cycloaddition has been reported. The structures of newly
synthesized compounds were confirmed by IR, 1H NMR, 13C NMR, HRMS and screened
for in vitro antimicrobial activity against Staphylococcus aureus (Gram positive bacteria),
Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes (Gram negative
bacteria); Candida albicans and Aspergillus niger (fungi). Some of the synthesized
compounds were found to exhibit good potency against above tested microbial strains.
Moreover, to study the binding interactions, docking simulation of broadly active
compound 3x was also carried out against E. coli dihydropteroate synthase enzyme.
1

Graphical Abstract
KEYWORDS: Antimicrobial activity; 1,4-Disubstituted 1,2,3-triazoles; Huisgen 1,3-
dipolar cycloaddition; Sulfonamides
INTRODUCTION
Nowadays, a steady increase in various infectious diseases has been observed in society
due to the growing number of drug resistant microbials. This aroused a substantial need
for the development of new antimicrobial agents with significant biological potential to
fight against drug resistant pathogens. Therefore, the triazoles, an active class of
heterocyclic compounds endowed with wide spectrum of biological activities [1,2]
attracted the attention of researchers.
1,2,3-Ttriazoles are one of the important category of active pharmaceuticals owing to the
well suited structure for biological system. These triazoles can easily be conjugated with
biological targets through dipole-dipole interactions and hydrogen bonding.[3] The
substituted 1,2,3-triazoles reflects widespread therapeutic uses such as antimicrobial,[4–
2

7] antiviral,[8] antihistaminic,[9] anticancer,[10] anti-HIV,[11] antitubercular,[12]
antiprotozoal,[13] anti-inflammatory[14] , anticonvulsant[15] etc.
1,2,3-Triazole moiety reflects stability against oxidative and reductive conditions as well
as acidic and basic hydrolysis.[16] 1,2,3-triazoles can be synthesized by various
methods.[17] However, the method discovered independently by Sharpless[18] and
Meldal[19] involving 1,3-dipolar cycloaddition between terminal alkyne and azide
using Copper(I) as a catalyst for the synthesis of 1,4-disubstituted 1,2,3-triazoles is the
best approach owing to its selectivity over thermally induced Huisgen classical
approach.[20] This Copper(I) catalyzed method[21] has been recognized) as one of the
prime click reaction and received considerable attention due to its regiospecificity,
quantitative yield and capacity to tolerate a wide variety of other functional groups.
Moreover, importance of click reaction has also been recognized in synthesis of
nanotubes,[22] enzymes,[23] dendrimers,[24] cyclic peptides,[25] peptide conjugation,[26]
liquid crystals[27] etc.
Because of the extensive significance of 1,2,3-triazoles, we focused the synthesis of some
1,4-disubstituted 1,2,3-triazoles (3a–3x) containing sulfonamide functionality through
Copper(I) catalyzed 1,3-dipolar cycloaddition between terminal alkynes and azides. All
the newly synthesized triazole derivatives were well characterized by various
spectroscopic techniques i.e. FTIR, 1H NMR, 13C NMR, HRMS and also evaluated for
antimicrobial activity against Staphylococcus aureus, Escherichia coli, Klebsiella
pneumoniae, Enterobacter aerogenes, Candida albicans and Aspergillus niger.
3

Molecular docking studies reveal valuable information about the close proximity between
the molecules and biological targets.[28] Therefore, in order to gain insight into the
binding modes and most plausible mechanism of action, docking simulation of broadly
active compound 3x was also performed against E. coli dihydropteroate synthase
enzyme.
RESULTS AND DISCUSSION
Chemistry
The synthetic route for the preparation of target compounds (3a–3x) has been outlined in
Scheme 1. For the convenient synthesis of sulfonamide linked 1,4-disubstituted 1,2,3-
triazoles, aromatic sulfonyl chlorides were taken as starting material. Various terminal
alkynes (1a–1e) were prepared from aromatic sulfonyl chlorides and 1,1-
dimethylpropargylamine in dichloromethane in the presence of 4-
(Dimethylamino)pyridine. After this the reaction between terminal alkynes (1a–1e) and
aromatic azides in the presence of copper sulphate pentahydrate and sodium ascorbate
lead to desired triazoles (3a–3x) in good yields. Aromatic azides were obtained in situ by
the reaction between aromatic bromides (2a–2e) and sodium azide, according to
reported procedure.[29]
The synthesized triazoles were well characterized by various spectroscopic techniques
i.e. IR, 1H NMR, 13C NMR, HRMS. The IR spectra of the synthesized compounds
displayed absorption bands in the region at 3233–3272 cm-1 and 3115–3152 cm-1 due to
the N–H and C–H stretching vibrations of triazole ring, respectively. The absorption
4

bands owing to the S=O asymmetric stretching and symmetric stretching of sulfonamide
were observed in the region 1307–1335 cm-1 and 1142–1157 cm-1, respectively. In 1H
NMR spectra of compounds, characteristic singlet appeared in the region of δ 7.00–7.45
indicating the presence of triazolyl proton. Another characteristic singlet was displayed in
the region of δ 1.60–1.69 which was attributed to the six protons of the two aliphatic
methyl groups. The signal due to the N-H proton exhibited in the range of δ 5.26–
6.01 Moreover, in 13C NMR spectra, appearance of signals in the region of δ 141.0–143.0
and δ 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
were found in accordance with theoretically predicted molecular masses.
Antimicrobial Activity
All the synthesized 1,4-disubstituted 1,2,3-triazole derivatives (3a–3x) were screened for
in vitro antimicrobial activity against one gram positive bacterial strain viz.
Staphylococcus aureus (MTCC 3160), three gram negative bacterial strain viz.
Escherichia coli (MTCC 443), Klebsiella pneumoniae (NCDC 138), Enterobacter
aerogenes (NCDC 106) and two fungal strains viz. Candida albicans (MTCC 227) and
Aspergillus niger (MTCC 282) by standard serial dilution technique.[30] Norfloxacin and
Fluconazole were used as reference drugs for antibacterial and antifungal strains,
respectively. The activity results are presented as minimum inhibitory
concentrations (MIC) in terms of μmol/mL.
5

Results of antibacterial activity are presented in Table 1. The synthesized triazoles were
found to possess average to good activity against bacterial strains used for present
study. Compounds 3e and 3x displayed overall good bactericidal efficiency against
tested bacterial strains. Compounds 3e, 3h, 3v and 3x (MIC 0.0311, 0.0270, 0.0291 and
0.0280 μmol/mL respectively) against S. aureus; 3e, 3h, 3j, 3s, 3v and 3x (MIC 0.0311,
0.0270, 0.0260, 0.0290, 0.0291 and 0.0280 μmol/mL respectively) against E. coli; 3c, 3e,
3j, 3n, 3s and 3x (MIC 0.0325, 0.0311, 0.0260, 0.0301, 0.0290 and 0.0140 μmol/mL
respectively) against K. pneumoniae; 3c, 3d, 3e, 3h, 3j, 3m, 3n, 3s, 3u, 3v and 3x (MIC
0.0650, 0.0135, 0.0623, 0.0540, 0.0520, 0.0627, 0.0301, 0.0579, 0.0602, 0.0582 and
0.0560 μmol/mL respectively) against E. aerogenes exhibited significant antibacterial
potency in comparison to reference drug.
Results clearly depicted that as the length of carbon chain at N1 position of triazole ring
increased, antibacterial potency was also increased and nitro substituted triazole
derivatives were found to be good antibacterial agent as compared to the methyl
substituted triazoles.
Antifungal activity results are presented in Table 2. Among the synthesized triazole
derivatives, compounds 3e and 3x (MIC 0.0311 and 0.0140 μmol/mL, respectively)
against C. albicans and compound 3x (MIC 0.0070 μmol/mL) against A. niger exhibited
excellent activity as compared to reference drug. Compounds 3s and 3v (MIC 0.0579 and
0.0582 μmol/mL, respectively) were found to possess comparable activity against C.
albicans.
6

It has been revealed from the results that compounds containing electron withdrawing
NO2 group on phenyl ring displayed better inhibitory activity against tested fungal strains
as compared to the compounds containing methyl substitutent on phenyl ring. Increase in
the length of carbon chain at N1 position of triazole ring also improved antifungal activity
against both the fungal strains.
Docking Studies
The docking simulations of broadly active compound 3x were carried out against active
site of E. coli dihydropteroate synthase for ascertaining the probable mechanism of action
and binding interactions responsible for bactericidal activity of the compounds under
study. This enzyme was chosen because it is target for antibacterial action of
sulfonamides and the compounds under study also contain sulfonamide group. The 3D
structure of the enzyme was retrieved from RCSB Protein Data Bank (PDB ID: 1 AJ0)
and Autodock Vina docking program[31] was used for docking studies.
Interestingly, the compound 3x oriented itself in a way as to act as dual site inhibitor. The
sulfonamide portion was anchored at the binding site of sulfanilamide and the other
portion containing triazole tethered phenyl ring went deep into the active site where
dihydropteridine binds (Fig. 1). The binding orientation of the compound 3x exhibited
various types interactions with the active site residues (Fig. 2). The oxygen atom of nitro
group present at the para position to the sulfonamide group displayed hydrogen bond
interactions with Arg63 and Arg220. The phenyl ring attached to the sulfonamide group
7

was involved in pi-cation interactions with residue Arg63. The oxygen atom of
sulfonamide group made hydrogen bond with Ser222 while nitrogen atom present in
triazole ring created hydrogen bond with Thr62. The phenyl ring attached directly to
triazole ring was sandwiched between Phe190 and Arg255 through pi-pi T-shaped and pi-
cation interactions, respectively. The nitro group attached at para position of this phenyl
ring showed hydrogen bond interactions with Asn115. The residue Arg63 was also
involved in binding with sulfanilamide ligand while residues Thr62, Asn115 and Arg255
were engaged in interactions with dihydropteridine ligand. Therefore, it can be said that
the compound under study successfully inhibits the enzyme dihydropteroate synthase.
CONCLUSION
In the present case, a convenient synthesis of sulfonamide linked 1,4-disubstituted 1,2,3-
triazoles (3a–3x) was carried out via click reaction between various terminal alkynes and
aromatic azides. The synthesized triazoles were examined for in vitro antimicrobial
evaluation against Staphylococcus aureus (Gram positive bacteria), Escherichia coli,
Klebsiella pneumoniae, Enterobacter aerogenes (Gram negative bacteria); Candida
albicans and Aspergillus niger (fungi). Among all the synthesized triazole derivatives,
compound 3x displayed significant antimicrobial efficiency against all tested strains,
while compound 3e was also found to be more potent against all tested bacterial strains
as well as Candida albicans compared to reference drugs. The docking studies depicted
that compound 3x inhibits enzyme E. coli dihydropteroate synthase through hydrogen
bonding, pi-cation interactions and pi-pi interactions.
8

EXPERIMENTAL
Chemistry
The starting materials were purchased from Sigma-Aldrich, Alfa-Aesar, Hi-Media and
used without any further purification. All the solvents used were distilled. Nutrient broth
and Sabouraud dextrose broth used in antimicrobial activity evaluation were obtained
from Hi-Media, Mumbai. Melting points (ºC) of the synthesized compounds were
determined by open capillaries and are uncorrected. The IR spectra were recorded on
SHIMAZDU IR AFFINITY-I FT-IR spectrometer using potassium bromide (KBr)
powder and values are given in cm-1. The 1H NMR spectra and 13C NMR were recorded
on BRUKER AVANCE II 400 MHz spectrometer at 400 MHz and 100 MHz respectively
in CDCl3 and chemical shifts (δ) are given in parts per million. Coupling constant (J)
values were observed in Hertz (Hz). Thin layer chromatography (TLC) was used to
monitor the reaction and to check the purity of compounds by using silica gel plates (SIL
G/UV254, ALUGRAM). High resolution mass spectra (HRMS) were observed on Bruker
micro TOF Q-II spectrometer.
Typical Procedure For The Synthesis Of N-(2-(1-Benzyl-1H-1,2,3-Triazol-4-
Yl)Propan-2-Yl)Benzenesulfonamide (3a)
The terminal alkyne i.e. N-(2-methylbut-3-yn-2-yl)benzenesulfonamide (1a) was
synthesized by dropwise addition of 1,1-dimethylpropargyl amine (1.0 mmol) to the
stirred solution of benzyl sulfonylchloride (1.0 mmol) in dry dichloromethane using 4-
(Dimethylamino)pyridine (1.0 mmol) as base at 0–4 ºC and stirring was continued for
2–3 h. After the completion of reaction, dilute hydrochloric acid was added; compound
9

was extracted with dichloromethane and the solvent was distilled to get the desired
product.
Afterwards benzyl bromide (1.0 mmol) (2a) and aqueous sodium azide (3.0 mmol) were
added in dimethylformamide at 25–40 ºC and continued stirring for half an hour. To
this solution, terminal alkyne (1.0 mmol) (1a), aqueous copper sulphate pentahydrate (10
mol %), sodium ascorbate (20 mol %) were added with continuous stirring and heating at
same temperature for 12 h. After the completion of reaction, ammonia solution was
added to the reaction mixture and extracted with ethyl acetate. Organic layer was
separated and dried with anhydrous sodium sulphate, filtered and reduced under vaccum
to obtain crude product (3a). This crude product was purified by column
chromatography.
Spectral Data
White solid; yield: 82 %; m.p.: 152–156 ºC; FT-IR (KBr): νmax = 3267 (N-H str.), 3119
(C-H str., triazole ring), 2982 (C-H str., aliphatic), 1597, 1452 (C=C str., aromatic ring),
1327 (S=O asym. str., sulfonamide), 1151 (S=O sym. str., sulfonamide) cm-1; 1H NMR
(400 MHz, CDCl3): δ = 1.64 (s, 6H, CH3), 5.38 (s, 2H, NCH2), 5.59 (s, 1H, NH), 7.24 (s,
1H, C-H triazole), 7.25–7.27 (m, 2H, Ar-H), 7.33–7.41 (m, 5H, Ar-H), 7.45 (t, 1H, Ar-H,
J = 8.0 Hz), 7.71 (d, 2H, Ar-H, J = 8.0 Hz) ppm; 13C NMR (100 MHz, CDCl3): δ = 28.8,
53.7, 53.9, 120.1 (C5 triazole), 126.8, 128.1, 128.5, 128.7, 129.0, 131.9, 134.3, 142.1 (C4
triazole), 152.6 ppm; HRMS (m/z) calculated for C18H20N4O2S [M+H]+: 357.1341.
Found: 357.1385
10

General Procedure For In Vitro Antimicrobial Evaluation
The newly synthesized triazole derivatives were evaluated for their in vitro antimicrobial
evaluation against one gram positive bacterial strain viz. Staphylococcus aureus (MTCC
3160), three gram negative bacterial strain viz. Escherichia coli (MTCC 443), Klebsiella
pneumoniae (NCDC 138), Enterobacter aerogenes (NCDC 106) and two fungi viz.
Candida albicans (MTCC 227) and Aspergillus niger (MTCC 282) by standard serial
dilution technique.[30] Initially, weighed amount of synthesized compounds (2.0 mg of
compound in 10 mL of DMSO) were dissolved in DMSO to get the stock solution of 200
µg/mL concentration. Fresh nutrient broth was used as a culture media for bacterial
strains and potato dextrose broth for fungal strains. One mL of nutrient broth was taken in
each test tube. After that one mLof stock solution is added in one test tube to get the
solution of 100 µg/mL concentration. From this solution, through serial dilution
technique, concentration of 50 to 3.12 µg/ml was obtained in other test tubes. After
that 0.1 mL of respective microorganism in sterile saline was aseptically inoculated in
each test tube and then incubated at 37 ± 1 ºC for 24 h (bacteria), 37 ± 1 ºC for 48 h (C.
albicans) and 25 ±1 ºC for 7 days (A. niger). Norfloxacin and Fluconazole were used as
reference drugs for antibacterial and antifungal strains, respectively and evaluated under
similar experimental conditions. Results were recorded visually in terms of Minimum
inhibitory concentration (MIC, µmol/mL).
Docking Simulations
11

The procedure for docking simulations was followed according to the protocols reported
by.[32] 3D structures of the molecules were made with Marvin Sketch 5.10.[33] The X-ray
crystallographic structure of E. coli dihydropteroate synthase along with co-crystallized
ligand sulfanilamide (SAN) and 2-amino-6-hydroxymethyl-7,8-dihydro-3H-pteridin-4-
one (PH2) (PDB ID: 1AJ0) was taken from Brookhaven Protein Databank
(http://www.rcsb.org/pdb). The enzyme was prepared with UCSF Chimera1.10.[34]
Dunbrack rotamer library[35] and Antechamber[36] were used to complete imperfect side
chains and to calculate Gasteiger charges. AutoDock tools[37] was used to create pdbqt
files.
AutoDock Vina was employed for docking studies. The Vina search space chosen was
center_x = 42.1600369472, center_y = 3.14416779475, center_z = 7.56991261289,
size_x = 18.7253852608, size_y = 21.9116364666, size_z = 18.5288609387. The
exhaustiveness for docking was set to be 8.
Redocking of co-crystallized ligands SAN and PH2 was performed for validation of
docking protocols. The root-mean square deviation (RMSD) between the conformations
of the SAN and PH2 from AutoDock Vina and that from the X-ray crystal structure was
less than 2Å showing that the chosen protocols are accurate for docking studies against
this enzyme. The same protocols were used for performing molecular docking of the
compound ASC into the binding site of dihydropteroate synthase. Results were
photographed with the aid of PyMOL[38] and Discovery Studio 4.0.[39]
12

ACKNOWLEDGEMENTS
Authors are highly thankful to University Grants Commission, New Delhi for financial
assistance.
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16

Table 1 In vitro antibacterial activity of 1,4-disubstituted 1,2,3-triazoles (3a–3x).
Compound
Minimum inhibitory concentration (MIC, µmol/mL)
Gram positive bacteria Gram negative bacteria
S. aureus
0.1403
0.0675
0.0650
0.1350
0.0311
0.2297
0.0556
0.0270
0.2225
0.0520
0.1350
0.1300
0.0627
0.0602
0.1294
0.1248
0.0603
0.0624
0.0579
E. coli K. pneumoniae E. aerogenes
0.2806 0.1403
0.1350 0.0675
0.0650 0.0325
0.1350 0.0675
0.0311 0.0311
0.1149 0.1149
0.0556 0.0556
0.0270 0.0540
0.0556 0.1113
0.0260 0.0260
0.2699 0.2699
0.1300 0.1300
0.0627 0.0627
0.0602 0.0301
0.1294 0.1294
0.0624 0.1248
0.0603 0.0603
0.0624 0.1248
0.0290 0.0290
0.2806
0.1350
0.0650
0.0135
0.0623
0.1149
0.1113
0.0540
0.2225
0.0520
0.2699
0.1300
0.0627
0.0301
0.2588
0.1248
0.1206
0.1248
0.0579
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
17

0.1246
0.0602
0.0291
0.1203
0.0280
0.0391
0.1246 0.0623
0.0602 0.0602
0.0291 0.0582
0.0602 0.0602
0.0280 0.0140
0.0391 0.0391
0.1246
0.0602
0.0582
0.1203
0.0560
0.0783
3t
3u
3v
3w
3x
Norfloxacin
18

Table 2 In vitro antifungal activity of 1,4-disubstituted 1,2,3-triazoles (3a–3x).
Compound
Minimum inhibitory concentration (MIC, µmol/mL)
C. albicans
0.1403
0.0675
0.0650
0.0675
0.0311
0.2297
0.0556
0.0540
0.1113
0.0520
0.1350
0.0650
0.0627
0.0602
0.2588
0.1248
0.0603
0.1248
0.0579
0.1246
A. niger
0.1403
0.0675
0.0325
0.0337
0.0156
0.0574
0.1113
0.0540
0.1113
0.0520
0.1350
0.0650
0.0314
0.0301
0.1294
0.0624
0.0603
0.1248
0.0290
0.1246
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
19

0.0602
0.0582
0.2407
0.0140
0.0408
0.0602
0.0291
0.1203
0.0070
0.0102
3u
3v
3w
3x
Fluconazole
20

Scheme 1. Synthesis of 1,4-disubstituted 1,2,3-triazoles with sulfonamide functionality
(3a–3x).
21

Figure 1. Compound 3x (cyano) docked in binding site of enzyme E. coli
dihydropteroate synthase along with co-crystallized ligands sulfanilamide (yellow) and 2-
amino-6-hydroxymethyl-7,8-dihydro-3H-pteridin-4-one (green).
22

Figure 2. Binding interactions (dotted lines) of compound 3x in active site of enzyme E.
coli dihydropteroate synthase (Hydrogen bond: green, Pi-cation interactions: yellow and
Pi-pi interactions: pink).
23