Regioselective synthesis and antimicrobial evaluation of some thioether–amide linked 1,4-disubstituted 1,2,3-triazoles

Article abstract of DOI:10.1080/00397911.2016.1265983

A series of 1,4-disubstituted 1,2,3-triazoles having thioether as well as amide linkage were synthesized from aryl(prop-2-yn-1-yl)sulfanes and 2-azido-N-substituted acetamides through Cu(I) catalyzed click reaction. Structures of newly synthesized compounds (3a–3x) were confirmed by spectral techniques like FTIR,¹H NMR,¹³C NMR, and HRMS. The synthesized triazoles were evaluated for in vitro antimicrobial activity against Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Staphylococcus aureus, Candida albicans, and Aspergillus niger. Compounds 3m and 3q displayed appreciable broad spectrum antimicrobial activity against tested microbial strains. The nanoformulations of compounds 3m and 3q were also prepared and examined against one bacterial strain and one fungal strain.

Full text of DOI:10.1080/00397911.2016.1265983

Regioselective Synthesis and Antimicrobial Evaluation of Some Thioether-Amide
Linked 1,4-Disubstituted 1,2,3-Triazoles
C. P. Kaushik1, Ashima Pahwa1, Rajesh Thakur2, Pawan Kaur2
1Department of Chemistry, Guru Jambheshwar University of Science & Technology,
Hisar, Haryana, India 2Department of Bio & Nanotechnology, Guru Jambheshwar
University of Science & Technology, Hisar, Haryana, India
Abstract
A series of 1,4-disubstituted 1,2,3-triazoles having thioether as well as amide linkage was
synthesized from aryl(prop-2-yn-1-yl)sulfanes and 2-azido-N-substituted acetamides via
Cu(I) catalyzed click reaction. Structures of newly synthesized compounds (3a–3x) were
confirmed by spectral techniques like FTIR, 1H NMR, 13C NMR and HRMS. The
synthesized triazoles were evaluated for in vitro antimicrobial activity against
Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Staphylococcus
aureus, Candida albicans and Aspergillus niger. Compounds 3m and 3q displayed
appreciable broad spectrum antimicrobial activity against tested microbial strains. The
nanoformulations of compounds 3m and 3q were also prepared and examined against one
bacterial strain and one fungal strain.
Graphical Abstract
1

KEYWORDS: Click reaction; 1,4-Disubstitued 1,2,3-triazoles; Antibacterial activity;
Antifungal activity
INTRODUCTION
Over the past few years, the instances of pathogenic microbial resistances to the available
drugs are increasing, throwing a challenge to chemists for the development of broad
spectrum drugs with better efficacy.[1] Triazoles, the five membered heterocycles are of
significant interest because of their role in designing of various privileged medicinal
scaffolds.[2] In this sequence, 1,2,3-triazoles having capability of interacting with
biological targets through dipole-dipole interactions and hydrogen bonding[3] attracted the
thoughts of researchers.
Disubstituted 1,2,3-triazoles possess key importance owing to their remarkable biological
activities like microbicidal,[4–7] anti-HIV,[8,9] anti-inflammatory,[10] antilieshmanial,[11]
antihistaminic, [12] anticancerous,[13,14] antitubercular,[15] antiprotozoal,[16] antiviral[17] etc.
1,4-Disubstituted 1,2,3-triazoles also found applications in polymers,[18] material
science,[19] and agrochemicals.[20]
Earlier, disubstituted 1,2,3-triazoles were synthesized by Huisgen’s method[21] involving
reaction of terminal alkynes with organic azides at elevated temperature. Need for the
modification of this process aroused because of its poor regioselectivity, reflected in form
of mixture of 1,4 and 1,5-disubstituted 1,2,3-triazoles. Use of copper(I) as catalyst by
Sharpless[22] and Meldal[23] in Huisgen’s method resulted in synthesis of selective 1,4-
2

disubstituted 1,2,3-triazoles. This process is one of the key click reactions and has
received significant attention of chemists because of its regioselectivity, nominal reaction
conditions, generation of inoffensive byproducts and use of readily available solvents.
Further, the therapeutic action of many drugs is limited due to poor bioavailability,
solubility, in vivo unstability, unspecific distribution, fluctuations of drug level in
plasma[24] etc. Nanotechnological tools have rendered possibilities to overcome these
problems by means of targeted and sustained release of drugs.[25] Further, the suitably
designed nanoparticles can reach less accessible sites in the body by escaping
phagocytosis. Sustained release of drugs from nanoparticles help to maintain therapeutic
action of drugs for a longer time and stabilize its level in bloodstream. This is achieved
by encapsulation of drug in polymer matrix to restrict its instant availability and drug will
find its way as the matrix degrades slowly. This helps in lowering the dose and frequency
of administration of drug.[26,27] Biocompatible and biodegradable polymers such as
sodium-alginate and chitosan have been extensively used for encapsulation of drug due to
their properties of an ideal carrier for drug delivery.[28,29]
Herein, we report the synthesis of some thioether-amide linked 1,4-disubstituted 1,2,3-
triazoles (3a–3x) through click reaction between aryl(prop-2-yn-1-yl)sulfanes and 2-
azido-N-substituted acetamides. The structures of the synthesized compounds were
characterized by various spectral techniques i.e. FTIR, 1H NMR, 13C NMR and HRMS.
The synthesized compounds were screened for antimicrobial activities against
3

Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Staphylococcus
aureus, Candida albicans and Aspergillus niger.
Further, the nanoformulations (NFs) of broadly active compounds were prepared and
evaluated against one bacterial strain (Klebsiella pneumoniae), one fungal strain
(Candida albicans).
RESULTS AND DISCUSSION
Chemistry
Thioethereal terminal alkynes i.e. aryl(prop-2-yn-1-yl)sulfanes (1a–1e) were prepared by
reaction of aromatic thiols with propargyl bromide in the presence of potassium
carbonate in dimethylformamide. 2-Bromo-N-substituted acetamides (2a–2e) were
synthesized by reaction of aromatic amines and bromoacetyl bromide in dichloromethane
using potassium carbonate as base. The targeted 1,4-disubstituted 1,2,3-triazoles (3a–3x)
were synthesized from the reaction of aryl(prop-2-yn-1-yl)sulfanes (1a–1e) and 2-azido-
N-substituted acetamides (which were generated in situ from the reaction of 2-bromo-N-
substituted acetamides (2a–2e) with sodium azide) in the presence of copper sulphate
pentahydrate and sodium ascorbate in dimethylformamide:water (Scheme 1).
The synthesized 1,4-disubstituted 1,2,3-triazoles (3a–3x) were characterized by FTIR, 1H
NMR, 13C NMR spectroscopy and HRMS. In IR spectra, the formation of triazoles was
confirmed by absorption bands in the regions at 3109–3154 cm-1 (C-H str., triazole ring),
1663–1715 cm-1 (C=O str., amide) and 3221–3288 cm-1 (N-H str., amide).
4

In 1H NMR spectra of compounds (3a–3x), in most of the cases, a characteristic singlet
was observed in the region at δ 7.91–8.07 which was assigned to the triazolyl proton,
while the two protons of the methylene group attached to N1 of triazole ring resonated in
the range δ 5.24–5.55. Another singlet was also observed in the range δ 4.18–4.47 due to
the methylene group attached to C4 of triazole ring. The signal due to the N-H proton
appeared in the range δ 10.30–11.09. Further, aromatic protons resonated in the range of
δ 6.89–8.25. In 13C NMR spectra, two characteristic signals in the regions at δ 164.1–
165.8 and δ 125.2–125.5 were assigned to carbonyl carbon and C5 of the triazole ring,
respectively. However, the signal due to the C4 carbon was observed in the region at δ
143.5–144.0. The signal due to the aliphatic carbon attached to N1 of the triazole ring
exhibited in the region at δ 52.5–52.8 while carbon linked to the sulphur resonated in the
region at δ 27.4–29.8.
Results obtained from high resolution mass spectrometry were found to be in good
agreement with theoretical values.
Antimicrobial Activity
The synthesized triazoles (3a–3x) were tested for their in vitro antimicrobial activity
against four bacteria i.e. Escherichia coli (MTCC 443), Pseudomonas aeruginosa
(MTCC 424), Klebsiella pneumoniae (NCDC 138) and Staphylococcus aureus (MTCC
1809) using micro dilution method.[30] Tetracyclin dihydrochloride was used as reference
drug. Results of antibacterial activity are presented in Table 1 in terms of minimum
5

inhibitory concentration (μg/mL). Most of the synthesized compounds exhibited average
to good antibacterial activity. Compounds 3b, 3e, 3f, 3g, 3h, 3j, 3p, 3q, 3r, 3t against E.
Coli; 3c, 3f, 3g, 3l, 3m, 3q against P. aeruginosa; 3a, 3m, 3q against K. Pneumoniae; 3i,
3q against S. aureus displayed remarkable antibacterial activity in comparison to
reference drug.
All the newly synthesized triazole derivatives were also screened for their in vitro
antifungal activity against Candida albicans (MTCC 227) and Aspergillus niger (MTCC
282) using micro dilution and mycelium inhibition method, respectively.[30,31] Results of
antifungal evaluation have been presented in Table 1. Ketoconazole was used as a
reference drug. The compounds 3a–3g, 3i –3k, 3m, 3q–3s and 3u–3w were found to
possess excellent activity against C. albicans. The compounds 3m, 3p and 3q displayed
good activity against A. niger.
Based on the results of antimicrobial activity, broadly active compounds 3m and 3q were
selected for preparation of nanoformulations. For this aim, chitosan and sodium alginate
polymers were used with these compounds and their antimicrobial activity were
evaluated. Polymer nanoparticles alone (dummy) and also along with compounds (NFs)
were used for antimicrobial activity. Klebsiella pneumoniae and Candida albicans were
used as test microorganism for antimicrobial study. Results of antimicrobial activity of
nanoformulations of compounds 3m and 3q are presented in Table 2. It was observed that
nanoformulations showed higher antimicrobial activity than compound alone. So this
may be a promising step to enhance biological activities of triazole compounds.
6

Particle Size Analysis Of Nanoformulations
Particle size analysis was carried out by using Dynamic Light Scattering (DLS)
technique. The intensity graph of 3m and 3q loaded chitosan alginate nanoparticles are
shown in Fig. 1 and Fig. 2, respectively. Z-average size for 3m and 3q nanoparticles were
172.5 nm and 122.0 nm, respectively. Double peaks were shown due to the presence of
particles of two different sizes. The graph reflects the intensity distribution of particles.
Bigger particles scatter more light in comparison to smaller particles. Hence, for intensity
based distribution, percent intensity is more in case of bigger particles although they are
less in number and vice versa.
Transmission Electron Microscopy Of Nanoformulations
Transmission electron microscopy revealed spherical morphology of nanoparticles (Fig. 3
and Fig. 4). For both samples, particle size was found in the range 9–30 nm, which was
less than the particle size measured with dynamic light scattering (DLS) as expected. The
reason is attributed to the fact that DLS measurements consider the ionic environment of
the particle whereas TEM measures the particle size in isolated environment.[32]
CONCLUSION
In the present work, a series of 1,4-disubstituted 1,2,3-triazoles (3a–3x) has been
synthesized through convenient and straightforward approach in form of Cu(I) catalyzed
click reaction between thioethereal terminal alkynes and azides containing amide
linkage. These synthesized triazoles were evaluated for in vitro antimicrobial activity
7

against Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae,
Staphylococcus aureus, Candida albicans and Aspergillus niger. Among the tested
triazoles, compounds 3e–3g, 3j and 3q against E. Coli; 3c, 3g, 3m and 3q against P.
aeruginosa; 3a, 3m and 3q against K. Pneumoniae; 3i and 3q against S. aureus; 3b, 3d
and 3e against C. albicans showed noteworthy activity as compared to reference drug
used. Compounds 3m and 3q were found to be most active against all tested strains as
compared to reference drug and therefore selected for their nanoformulations. These
nanoformulations displayed enhanced antimicrobial activity in comparison to compound
alone.
EXPERIMENTAL
Chemistry
All the reagents and solvents were purchased from Alfa-Aesar, Sigma-Aldrich, Hi-Media
and used without any purification. Melting points (ºC) of synthesized compounds were
taken by open capillary method and are uncorrected. The FTIR spectra were observed on
SHIMAZDU IR AFFINITY-I FT-IR spectrometer using potassium bromide powder. The
1H NMR spectra and 13C NMR spectra were recorded on BRUKER AVANCE II 400
MHz spectrometer at 400 MHz and 100 MHz, respectively in DMSO-d6 (chemical shift
in δ, ppm). Coupling constant (J) values were observed in Hertz (Hz). HRMS were
obtained on Waters Micromass Q-Tof Micro (ESI) spectrometer and values were quoted
in m/z. To check the purity of compounds and completion of reactions, thin layer
chromatography (TLC) was employed using readymade silica gel plates (SIL G/UV254,
ALUGRAM) and visualized under ultraviolet lamp.
8

Typical Procedure For The Synthesis Of N-Phenyl-2-(4-((Phenylthio)Methyl)-1H-
1,2,3-Triazol-1-Yl)Acetamide (3a)
Phenyl(prop-2-yn-1-yl)sulfane (1a) was synthesized by addition of propargyl bromide
(1.0 mmol) to the benzenethiol (1.0 mmol) in N,N-dimethylformamide in the presence of
potassium carbonate (3.0 mmol) at 10–25 ºC temperature with constant stirring for 5–6 h.
For the synthesis of 2-bromo-N-phenylacetamide (2a), bromoacetylbromide (1.2 mmol)
was added dropwise into the stirred solution of aniline (1.0 mmol) in dichloromethane in
the presence of potassium carbonate (1.5 mmol) at 0–5 ºC for 15 minutes, then added
water, filtered the precipitated solid and dried to get desired compound (2a).
Synthesis of compound (3a) was carried out by dissolving phenyl(prop-2-yn-1-yl)sulfane
(1a) and 2-bromo-N-phenylacetamide (1.0 mmol) (2a) in dimethylformamide, then added
aqueous sodium azide (3.0 mmol), aqueous copper sulphate pentahydrate (0.1 mmol)
and sodium ascorbate (0.4 mmol) at 25–40 ºC for 6–14 h. Progress of reaction was
monitored with TLC. After completion of reaction, ice cold water was added to reaction
mixture. Precipitated solid was filtered and washed with ammonia solution. Crude
product was purified by washing with ethyl acetate and dried under vaccum to get pure
product (3a) in high yield.
Spectral Data
White solid; yield: 93%; m.p.: 141–144 ºC; FTIR (KBr): νmax = 3278 (N-H str.), 3120 (C-
H str., triazole ring), 3058 (C-H str., aromatic ring), 2986 (C-H str., aliphatic), 1679
9

(C=O str., amide), 1605, 1553 (C=C str., aromatic ring) cm-1; 1H NMR (400 MHz,
DMSO-d6): δ = 4.33 (s, 2H, SCH2), 5.29 (s, 2H, NCH2), 7.09 (t, 1H, Ar-H, J=8.0 Hz),
7.19 (t, 1H, Ar-H, J=8.0 Hz), 7.30–7.35 (m, 4H, Ar-H), 7.40 (d, 2H, Ar-H, J=8.0 Hz),
7.58 (d, 2H, Ar-H, J=8.0 Hz), 8.02 (s, 1H, C-H triazole), 10.45 (s, 1H, N-H amide) ppm;
13C NMR (100 MHz, DMSO-d6): δ = 27.5, 52.7, 119.7, 124.2, 125.4 (C5 triazole), 126.3,
128.4, 129.4, 129.5, 136.5, 138.9, 143.8 (C4 triazole), 164.6 (C=O amide) ppm; HRMS
(m/z) calculated for C17H16N4OS [M+H]+: 325.1078. Found: 325.1128.
Synthesis Of Nanoformulations Of Compounds
Preparation Of Blank Chitosan-Alginate Nanoparticles
Nanoparticles were prepared using method reported by Li et al. with slight
modifications.[33] 10 mL of calcium chloride (3.81 mg/mL) was added to 50 mL of
sodium alginate solution (3mg/mL) (pH 5.1) and stirred for 0.5 h using magnetic stirrer.
After that 20 mL of chitosan (0.8 mg/mL in 1% v/v acetic acid) (pH 5.4) was added
dropwise and further stirred for 1 h.
Preparation Of Compound Loaded Chitosan-Alginate Nanoparticles
Two mL solution of compound (3m or 3q) was prepared in ethanol/water mixture (1:1,
4mg/mL) and incorporated into the calcium chloride solution during the preparation of
blank chitosan-alginate nanoparticles.
Characterization
Particle Size Analysis
10

Dynamic Light Scattering (DLS) was used to measure the average particle size. One mL
of nanosuspension was loaded into disposable clear particle sizing cuvette and scanned at
25 °C using the Zetasizer nano ZS 90 (Malvern instruments, Malvern, UK).
Transmission Electron Microscopy
Compound loaded nanoparticles were studied for their morphology using transmission
electron microscopy (TEM Morgagni 268D, Fei Electron Optics). Lyophilized
nanoparticles of compound were suspended in distilled water and dispersed ultrasonically
to separate individual particles. A drop of the suspension was loaded on carbon-coated
copper grids, air-dried and then observed by TEM.
Antimicrobial Studies
All the synthesized compounds (3a–3x) were accessed for their in vitro antimicrobial
activity against bacteria i.e. Escherichia coli, Pseudomonas aeruginosa, Klebsiella
pneumoniae, Staphylococcus aureus, and fungi i.e. Candida albicans, Aspergillus niger.
Results were recorded in terms of MIC (minimum inhibitory concentration). The
comparative evaluation of minimal inhibitory concentration (MIC) of all the compounds
against bacteria and C. albicans was performed by micro dilution method[30]
.
Tetracycline dihydrochloride and Ketoconazole were used as standard antibacterial and
antifungal drugs, respectively. For bacteria, fresh cultures were inoculated on nutrient
agar plates and incubated at 37 °C for 24 h; for C. albicans, fresh cultures were
inoculated on potato dextrose agar (PDA) plates and incubated at 30°C for 72 h, to obtain
single colonies, which were further inoculated into the experimental broth in B.O.D
11

incubator. To evaluate the minimum inhibitory concentration (MIC), two-fold serially
diluted synthesized compounds, well dispersed in 1 mL of stock solution (200µL DMSO
and 800µL of 0.1% tween solution in distilled water), starting from 2000 µg/mL to
62.5µg/mL, were tested. After incubation, absorbance was measured by
spectrophotometer (ELISA plate reader, Power WaveXS2).
Synthesized compounds were screened against fungus Aspergillus niger by observing the
percentage inhibition of mycelial growth.[31] Stock solutions were prepared by adding
10x103 µg/mL and 5x103 µg/mL and 2.5x103 µg/mL of compounds to distilled water at
room temperature and neutral pH. For activity against fungus A. niger, about 15 mL of
the Potato Dextrose Agar medium was poured into petri plates and allowed to solidify.
After solidification, 500 μL of stock solution was spread on them using a sterilized swab.
5 mm discs of 7-day-old culture of the test fungi were placed at the centre of the above
petri plates and incubated at 25±2ºC for 7 days.
After incubation the colony diameter was measured. For each treatment, three replicates
were maintained.
Nanoformulations of synthesized compounds 3m and 3q were also tested for their in
vitro antimicrobial activity against one bacterial strain i.e. Klebsiella pneumoniae and one
fungal strain i.e. Candida albicans by using the method described above.
ACKNOWLEDGEMENTS
12

Authors are highly thankful to University Grants Commission, New Delhi for financial
assistance.
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15

Table 1. Antimicrobial activity of compounds (3a–3x) in terms of MIC in μg/mL ×102.
Compound
Minimum Inhibitory Concentration (MIC, μg/mL ×102)
Escherich Pseudomon Klebsiell Staphylococc Candid Aspergill
ia coli
(MTCC
443)
as
a
us aureus
a
us niger
aeruginosa pneumon (MTCC
albica (MTCC
(MTCC
424)
ia
1809)
ns
282)
(NCDC
138)
12
(MTC
C 227)
10
5
20
18
20
22
15
15
12
18
20
15
19
21
21
20
20
20
20
10
15
20
13.5
10
15
15
20
14
11
10
14
15
20
15
15
18
18.5
15
15
15
12
20
20
15
15
20
18
100
100
100
50
3a
3b
3c
3d
3e
3f
18.5
16
10
5
15
15
5
50
20
15
12
18
12
15
15
18
12
20
22
100
100
50
20
3g
3h
3i
15
18
50
20
50
3j
20
50
3k
3l
20
50
12
25
3m
3n
3o
14
50
20
50
16

18
15
18
20
17.5
20
20
20
25
20
20
10
18
20
20
15
20
18
20
15
15
14
18
15
20
15
20
20
20
15
22
12.5
20
20
18
20
20
15
20
15
18
15
15
15
17.5
15
10
15
25
-
25
25
50
50
50
50
50
50
50
-
3p
3q
3r
3s
3t
3u
3v
3w
3x
Tetracyclin
dihydrochlori
de
Ketoconazole -
-
-
-
20
25
17

Table 2. Antimicrobial activity of nanoformulation of compound 3m and 3q in terms of
MIC in μg/ mL×102.
Compound
Minimum Inhibitory Concentration (MIC, μg/mL ×102)
Klebsiella pneumonia (NCDC 138) Candida albicans (MTCC 227)
12
8
12
5
3m
3m NF
3q
14
15
3q NF
9
10
Tetracycline
Dihydrochloride
Ketoconazole
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20
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Scheme 1. Synthesis of thioether-amide linked 1,4-disubstituted 1,2,3-triazoles (3a–3x)
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Figure 1. The intensity graph of 3m loaded chitosan alginate nanoparticles.
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Figure 2. The intensity graph of 3q loaded chitosan alginate nanoparticles.
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Figure 3. Transmission electron microscopy (TEM) image of nanoformulation of
compound 3m.
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Figure 4. Transmission electron microscopy (TEM) image of nanoformulation of
compound 3q.
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