Synthesis, characterization, and antimicrobial potential of some 1,4-disubstituted 1,2,3-bistriazoles

Article abstract of DOI:10.1080/00397911.2015.1056796

A convenient synthesis of some new 1,4-disubstituted 1,2,3-bistriazoles (3a-3f, 4a-4f, 6a-6b, 7a-7b) is reported via copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition of various terminal alkynes with 1,4-bis(azidomethyl)benzene and 1,6-diazidohexane.

Full text of DOI:10.1080/00397911.2015.1056796

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Synthesis, Characterization, and Antimicrobial
Potential of Some 1,4-Disubstituted 1,2,3-Bistriazoles
a
a
b
c
c
C. P. Kaushik , Krishan Kumar , Dharmendra Singh , S. K. Singh , Deepak Kumar Jindal & Raj
a
Luxmi
a
Department of Chemistry, Guru Jambheshwar University of Science & Technology, Hisar,
Haryana, India
b
Centre for Research & Development, IPCA Lab Ltd., Kandivali, Mumbai, Maharashtra, India
c
Department of Pharmaceutical Sciences, Guru Jambheshwar University of Science &
Technology, Hisar, Haryana, India
Accepted author version posted online: 03 Jun 2015.
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To cite this article: C. P. Kaushik, Krishan Kumar, Dharmendra Singh, S. K. Singh, Deepak Kumar Jindal & Raj Luxmi
2015): Synthesis, Characterization, and Antimicrobial Potential of Some 1,4-Disubstituted 1,2,3-Bistriazoles,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, DOI:
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1
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SYNTHESIS, CHARACTERIZATION, AND ANTIMICROBIAL POTENTIAL
OF SOME 1,4-DISUBSTITUTED 1,2,3-BISTRIAZOLES
1
1
2
3
C. P. Kaushik , Krishan Kumar , Dharmendra Singh , S. K. Singh , Deepak Kumar
3
1
Jindal Raj Luxmi
1
Department of Chemistry, Guru Jambheshwar University of Science & Technology,
2
Hisar, Haryana, India, Centre for Research & Development, IPCA Lab Ltd., Kandivali,
3
Mumbai, Maharashtra, India, Department of Pharmaceutical Sciences, Guru
Jambheshwar University of Science & Technology, Hisar, Haryana, India
Address Correspondence to: C. P. Kaushik, Email: kaushikcp@gmail.com
Abstract
A convenient synthesis of some new 1,4-disubstituted 1,2,3-bistriazoles (3a-3f, 4a-4f, 6a-
6
b, 7a-7b) is reported via copper (I) catalyzed Huisgen 1,3-dipolar cycloaddition of
various terminal alkynes with 1,4-bis(azidomethyl)benzene and 1,6-diazidohexane. The
1
13
synthesized compounds were characterized by spectral techniques viz. IR, H NMR, C
NMR, HRMS and tested in vitro for antimicrobial potential against Bacillus subtilis,
Staphylococcus aureus (Gram positive bacteria), Pseudomonas aeruginosa, Escherichia
coli (Gram negative bacteria), Candida albicans and Aspergillus niger (fungi). Among
the synthesized 1,4-disubstituted 1,2,3-bistriazoles, compounds 6a, 6b and 7b displayed
excellent antimicrobial potential against most of the tested strains.
1

Keywords Click reaction; 1,4-disubstituted 1,2,3-bistriazoles; Antibacterial activity;
Antifungal activity
INTRODUCTION
N-heterocycles constitute a class of biologically active molecules owing to their key
biological spectrum and applications as structural motif for designing of molecules of
[
1,2]
pharmaceutical interest.
present in numerous of life saving drugs.
immense chemotherapeutic importance as antiviral, antimicrobial,
Among these, triazoles are a versatile group of molecules
[
3,4]
Literature survey reveals that triazoles have
[5]
[6,7]
[
8]
[9]
[10]
[11]
[12]
antimicobacterial, anticancer, antitripanosomal, anti-HIV, antimalarial,
[
13]
[14]
[15]
[16]
analgesic, anti-inflammatory, antihypertensive, anticonvulsant and CNS
[
17]
[18]
depressant agents. A review by Haider et al. provides an excellent account of
diverse biological activity spectrum associated with 1,2,3-triazole moiety.
[
19]
Various methods are available for the synthesis of 1,2,3-triazoles, however, the
copper(I) catalyzed 1,3-dipolar cycloaddition of terminal alkynes with organic azides is
[
20]
one of the best method for regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles.
2

[
21]
[22]
This method was independently pioneered by Sharpless and Meldal in 2002 through
[
23]
dramatic modification in classical Huisgen 1,3-dipolar cycloaddition reaction. This
Sharpless-Meldal’s pioneered reaction has been pointed out as one of the premier click
reaction which attracted the chemist’s interest with salient features like modularity,
regioselectivity, high yields, purity and versatile chemical transformations. The
[24]
significance of click reaction can also be revealed in synthesis of liquid crystals,
[
25]
[26]
[27]
[28]
[29]
dendrimers, triazolophanes, peptidomimetics, cyclic peptides, nanotubes
[
30]
and ionic receptors.
Therefore, owing to widespread applications of triazoles, we focused the research work
on synthesis and biological evaluation of 1,4-disubstituted 1,2,3-triazoles for the thirst of
new potent antimicrobials. Earlier also, our research group synthesized 1,4-disubstituted
[
31-36]
1
,2,3-triazoles
having microbicidal activities. In continuation with our previous
work, various 1,4-disubstituted 1,2,3-bistriazoles (3a-3f, 4a-4f, 6a-6b, 7a-7b) have been
synthesized via copper(I) catalyzed click reaction of different terminal alkynes with 1,4-
bis(azidomethyl)benzene and 1,6-diazidohexane. To the best of our knowledge, all the
sixteen synthesized 1,4-disubstituted 1,2,3-bistriazoles are new. The synthesized
1
13
bistriazoles were characterized by spectroscopic techniques like IR, H NMR, C NMR,
HRMS and evaluated for their antimicrobial potential against Bacillus subtilis,
Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Candida albicans
and Aspergillus niger.
RESULTS AND DISCUSSION
3

Chemistry
,4-disubstituted 1,2,3-bistriazoles (3a-3f, 4a-4f, 6a-6b, 7a-7b) were synthesized via Cu
I) catalyzed click reaction of various terminal alkynes with 1,4-bis(azidomethyl)benzene
1
(
and 1,6-diazidohexane. 1,4-Bis(azidomethyl)benzene and 1,6-diazidohexane were
prepared in situ by the reaction of sodium azide with 1,4-bis(bromomethyl)benzene and
1
,6-dibromohexane, respectively.
[
35,36]
Benzoic acid prop-2-ynyl ester and its derivatives (1a-1e) were synthesized
reacting their corresponding aromatic acid chlorides with propargyl alcohol in
dichloromethane using N,N-dimethylaminopyridine as base, whereas, propargyl acrylate
1f) was purchased from Sigma Aldrich. The ester linked terminal alkynes (1a-1f) were
by
(
then reacted with 1,4-bis(bromomethyl)benzene and 1,6-dibromohexane in the presence
of sodium azide, copper sulphate pentahydrate and sodium ascorbate in
dimethylformamide-water to afford 1,4-disubstituted 1,2,3-bistriazoles 3a-3f and 4a-4f,
respectively (Scheme 1).
The benzofused N-heteroaromatic alkynes (5a-5b) were synthesized by reacting
benzotriazole/ benzimidazole with propargyl bromide in the presence of potassium
[
37]
carbonate using dimethylforamamide as solvent, as per literature procedure. The
synthesized alkynes (5a-5b) were then reacted with 1,4-bis(bromomethyl)benzene and
1
,6-dibromohexane in the presence of sodium azide, copper sulphate pentahydrate,
sodium ascorbate in dimethylformamide-water to furnish 1,4-disubstituted 1,2,3-
bistriazoles 6a-6b and 7a-7b, respectively (Scheme 2).
4

1
The synthesized 1,4-disubstituted 1,2,3-bistriazoles were characterized by IR, H NMR,
1
3
C NMR spectroscopy and HRMS. The formation of triazoles was confirmed by the
-1
appearance of absorption band in the region 3153-3109 cm in their IR spectra due to C-
1
H stretching vibrations of triazole rings. In the H NMR spectra, a characteristic singlet
resonated in the region δ 7.95-8.32 was attributed to triazolyl protons present on the C-5
1
3
of the triazole rings. Moreover, in the C NMR spectra of bistriazoles, signals appeared
in the region δ 124.2-126.6 and δ 141.8-143.4 owing to C-5 and C-4 of the triazole rings
also confirmed the formation of final products. The results obtained from high resolution
mass spectral analysis were found in accordance with their calculated molecular mass.
Antibacterial Activity
All the synthesized 1,4-disubstituted 1,2,3-bistriazoles (3a-3f, 4a-4f, 6a-6b, 7a-7b) were
tested in vitro for antibacterial activity against Bacillus subtilis, Staphylococcus aureus,
Pseudomonas aeruginosa and Escherichia coli. Double strength nutrient broth was used
as culture media. The antibacterial potential of bistriazoles was compared with standard
drug, ciprofloxacin and their minimum inhibitory concentration (MIC) values were
recorded in µmol/mL as shown in Table 1.
Antibacterial studies showed that the synthesized bistriazoles displayed average to
excellent performance against tested bacterial strains. Compounds 4f, 6a, 6b and 7b (MIC
0.0643, 0.0497, 0.0249 and 0.0520 µmol/mL respectively) exhibited good antibacterial
potential against Bacillus subtilis; compounds 3d, 4d, 6a, 6b, 7a and 7b (MIC 0.1670,
5

0
.1728, 0.0994, 0.0998, 0.1036 and 0.1040 µmol/mL respectively) displayed significant
activity against Staphylococcus aureus, whereas, compounds 6b, 7a and 7b (MIC 0.0499,
.0518 and 0.0520 µmol/mL respectively) have remarkable bactericidal efficacy against
0
Pseudomonas aeruginosa, while in case of Escherichia coli, compounds 4d, 6a, 6b, 7a
and 7b (MIC 0.0864, 0.0994, 0.0499, 0.1036 and 0.1040 µmol/mL respectively) emerged
as good antibacterial agents.
Antifungal Activity
The 1,4-disubstituted 1,2,3-bistriazoles (3a-3f, 4a-4f, 6a-6b, 7a-7b) were screened for
their in vitro antifungal activity against two fungal strains i.e. Candida albicans and
Aspergillus niger. Fluconazole was used as reference compound and sabouraud dextrose
broth as fungal culture media. The results were recorded in terms of MIC in µmol/mL of
the compounds as displayed in Table 2.
Results of antifungal evaluation indicated that the synthesized bistriazoles exhibited
excellent to moderate activity against tested fungal strains. Compounds 6a, 6b and 7b
(
MIC 0.0497, 0.0499 and 0.0520 µmol/mL respectively) displayed noteworthy fungicidal
potential against Candida albicans, while, compounds 3f, 6a, 6b and 7b (MIC 0.1224,
.0994, 0.0499 and 0.1040 µmol/mL respectively) came out as potent antifungal agents
0
against Aspergillus niger.
From the above antimicrobial evaluation, it has been shown that the presence of 1H-
benzotriazolyl and 1H-benzimidazolyl moiety on methylene carbon attached to C of the
4
6

triazole rings enhanced the antimicrobial potential of synthesized compounds against all
tested bacterial and fungal species. Moreover, replacement of benzoyl group by p-
nitrobenzoyl or acrylate also improved the microbicidal efficiency, although, displacement
of benzoyl group by p-toluoyl or p-methoxybenzoyl group resulted into decrease in
antimicrobial potency of the synthesized bistriazoles.
CONCLUSION
Presently, 1,4-disubstituted 1,2,3-bistriazoles were synthesized via copper(I) catalyzed
click reaction of various terminal alkynes with 1,4-bis(azidomethyl)benzene and 1,6-
diazidohexane. The synthesized bistriazoles were evaluated in vitro for antimicrobial
activity against Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeruginosa,
Escherichia coli, Candida albicans and Aspergillus niger. The compounds 6a, 6b against
Bacillus subtilis; 6a, 6b, 7a and 7b against Staphylococcus aureus; 6b against
Pseudomonas aeruginosa; 4d, 6b against Escherichia coli exhibited good antibacterial
activity. Moreover, compounds 6a, 6b and 7b appeared as better fungicidal agents against
both tested fungal strains. In nutshell, antimicrobial activity reflects the compounds 6a,
6
b and 7b as good antimicrobial agents.
EXPERIMENTAL
Typical Procedure For Synthesis Of (1,1'-(1,4-Phenylenebis(Methylene))Bis(1H-
1
,2,3-Triazole-4,1-Diyl))Bis(Methylene)Dibenzoate (3a).
[
35,36]
The synthesis
of benzoic acid prop-2-ynyl ester (1a) was carried out by reacting 0.23
mL of benzoyl chloride (2.0 mmol) with 0.14 mL of propargyl alcohol (2.4 mmol) using
7

2
45.0 mg of N,N-dimethylaminopyridine (2.0 mmol) as base in dry dichloromethane with
continuous stirring at 10 ºC for 4 h. The compound 3a was synthesized by reacting
63.96 mg of 1,4-bis(bromomethyl)benzene (2, 1.0 mmol) with 320.34 mg of benzoic
acid prop-2-ynyl ester (1a, 2.0 mmol) using 195.03 mg of sodium azide (3.0 mmol),
4.97 mg of copper sulphate pentahydrate (0.1 mmol) and 80.0 mg of sodium ascorbate
0.4 mmol) in dimethylformamide : water (8+2 mL) with continuous stirring at 45 ºC for
2 h (Scheme 1).
2
2
(
1
Spectral Data
Appearance: white solid; Yield: 91%; m.p.: 198-202 ºC; FT-IR (KBr) νmax/ cm : 3111
C-H str., triazole ring), 3062 (C-H str., aromatic ring), 1710 (C=O str., ester), 1600,
-1
(
1
521, 1446 (C=C str., aromatic ring), 1271 (C-O asym. str., ester), 1101 (C-O sym. str.,
1
ester); H NMR (400 MHz, DMSO-d , δ, ppm): 5.38 (s, 4H, NCH ), 5.60 (s, 4H, OCH ),
6
2
2
7
4
.34 (s, 4H, Ar-H), 7.52 (t, 4H, Ar-H, J=7.2 Hz), 7.66 (t, 2H, Ar-H, J=7.2 Hz), 7.95 (d,
1
3
H, Ar-H, J=7.2 Hz), 8.30 (s, 2H, C-H triazole); C NMR (100 MHz, DMSO- d , δ,
6
ppm): 52.9, 58.4, 125.4 (C triazole), 128.9, 129.3, 129.7, 129.8, 134.0, 136.4, 142.6 (C
5
4
+
triazole), 165.9 (C=O ester); HRMS (m/z) calculated for C H N O [M+H] : 509.1893.
2
8
24
6
4
Found: 509.1930.
Typical Procedure For Synthesis Of 1,4-Bis((4-((1H-Benzo[D][1,2,3]Triazol-1-
Yl)Methyl)-1H-1,2,3-Triazol-1-Yl)Methyl) Benzene (6a).
[
37]
The 1-(prop-2-ynyl)-1H-benzo[d][1,2,3]triazoles (5a) was synthesized by reacting
2
38.24 mg of 1H-benzo[d][1,2,3]triazole (2.0 mmol) with 0.21 mL of propargyl bromide
8

(2.4 mmol) using 552.0 mg of potassium carbonate (2.0 mmol) in dry
dimethylforamamide with stirring at 15 ºC for 8 h. The compound 6a was synthesized by
reacting 263.96 mg of 1,4-bis(bromomethyl)benzene (2, 1.0 mmol) with 314 mg of 1-
(prop-2-ynyl)-1H-benzo[d][1,2,3]triazole (5a, 2.0 mmol) using 195.03 mg of sodium
azide (3.0 mmol), 24.97 mg of copper sulphate pentahydrate (0.1 mmol) and 80.0 mg of
sodium ascorbate (0.4 mmol) in dimethylformamide : water (9+1 mL) with stirring at 35
ºC for 14 h (Scheme 2).
Spectral Data
-1
Appearance: creamy white solid; Yield: 80%; m.p.: 232-236 ºC; FT-IR (KBr) νmax/ cm :
3
1
5
136 (C-H str., triazole ring), 3064 (C-H str., aromatic ring), 2951 (C-H str., aliphatic),
1
622, 1496, 1458 (C=C str., aromatic ring); H NMR (400 MHz, DMSO-d , δ, ppm):
6
.54 (s, 4H, NCH ), 6.03 (s, 4H, NCH ), 7.31 (d, 4H, Ar-H, J=8.0 Hz), 7.40 (t, 2H, Ar-H,
2
2
J=7.6 Hz), 7.54 (t, 2H, Ar-H, J=7.6 Hz), 7.88 (d, 2H, Ar-H, J=8.4 Hz), 8.04 (d, 2H, Ar-
1
3
H, J=8.4 Hz), 8.27 (s, 2H, C-H triazole); C NMR (100 MHz, DMSO-d , δ, ppm): 43.3,
6
5
1
2.9, 111.3, 119.6, 124.7 (C triazole), 127.8, 128.8, 133.1, 136.3, 142.3 (C triazole),
5 4
+
45.7; HRMS (m/z) calculated for C H N [M+H] : 503.2124. Found: 503.2160.
2
6
22 12
Antimicrobial Activity
All synthesized 1,4-disubstituted 1,2,3-bistriazoles (3a-3f, 4a-4f, 6a-6b, 7a-7b) were
evaluated for their in vitro antimicrobial potential against Gram-positive bacteria i.e.
Bacillus subtilis (MTCC 441), Staphylococcus aureus (MTCC 7443); Gram-negative
bacteria i.e. Pseudomonas aeruginosa (MTCC 424), Escherichia coli (MTCC 1652) and
9

fungal strains i.e. Candida albicans (MTCC 227) and Aspergillus niger (MTCC 8189)
[38]
using two fold serial dilution method.
SUPPLEMENTAL MATERIAL
1
13
Full experimental detail, spectroscopic data and H NMR, C NMR, HRMS spectra of
all newly synthesized 1,4-disubstituted 1,2,3-bistriazoles can be accessed on the
publisher’s website.
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1
3

Table 1. Antibacterial activity of 1,4-disubstituted 1,2,3-bistriazoles (3a-3f, 4a-4f, 6a-6b,
7
a-7b) in terms of MIC (µmol/mL)
Gram-positive bacteria
Gram-negative bacteria
Escherichia
coli
Bacillus
subtilis
Staphylococcus Pseudomonas
Compound
aureus
(MTCC 7443)
0.9832
1.8636
0.8794
0.1670
0.9182
0.2448
0.5117
0.9678
1.8228
0.1728
0.3813
0.2574
0.0994
0.0998
0.1036
0.1040
0.1509
aeruginosa
(MTCC 424)
0.9832
0.9318
1.7588
0.1670
0.9182
0.1224
1.0234
0.9678
0.9114
0.0864
0.3813
0.1287
0.0994
0.0499
0.0518
0.0520
0.0377
(
MTCC 441)
(MTCC 1652)
0.4916
0.3727
0.4397
0.3342
1.8365
0.2448
1.0234
0.3871
1.8228
0.0864
0.9532
0.2574
0.0994
0.0499
0.1036
0.1040
0.0754
3
3
3
3
3
3
4
4
4
4
4
4
6
6
7
7
a
b
c
d
e
f
0.3933
0.3727
0.8794
0.0835
0.3673
0.1224
0.5117
0.4839
1.8228
0.0864
0.1906
0.0643
0.0497
0.0249
0.2072
0.0520
a
b
c
d
e
f
a
b
a
b
Ciprofloxacin 0.0377
1
4

Table 2. Antifungal activity of 1,4-disubstituted 1,2,3-bistriazoles (3a-3f, 4a-4f, 6a-6b,
7
a-7b) in terms of MIC (µmol/mL)
Candida albicans
Aspergillus niger
(MTCC 8189)
0.9832
Compound
(MTCC 227)
0.9832
0.9318
0.8794
0.4177
0.1836
0.1224
0.5117
0.9678
1.8228
0.1728
0.3813
0.1287
0.0497
0.0499
0.1036
0.0520
0.0408
3
3
3
3
3
3
4
4
4
4
4
4
6
6
7
7
a
b
c
d
e
f
1.8636
0.3518
0.3342
0.3673
0.1224
a
b
c
d
e
f
0.5117
1.9358
1.8228
0.3457
0.4766
0.2574
a
b
a
b
0.0994
0.0499
0.2072
0.1040
Fluconazole
0.0816
1
5

Scheme 1. Synthesis of ester linked 1,4-disubstituted 1,2,3-bistriazoles (3a-3f, 4a-4f)
1
6

Scheme 2. Synthesis of 1,4-disubstituted 1,2,3-bistriazoles containing benzofused
N-heteroaromatic functionalities (6a-6b, 7a-7b)
1
7