Synthesis, antimicrobial evaluation and docking study of triazole containing triaryl-1H-imidazole

Article abstract of DOI:10.1080/00397911.2019.1600192

An efficient route for the synthesis of triazole containing triaryl-1H-imidazole (3a–3r) was achieved involving multicomponent condensation of triazole aldehydes, ammonium acetate and 1,2-dicarbonyl compounds in glacial acetic acid. The structure of newly synthesized imidazoles was established by the FTIR, HRMS and NMR spectra. All the compounds displayed considerable antimicrobial activity against fungal and bacterial strains. The triazolyl imidazole 3p was substantially potent against P. aeruginosa (0.0113 μmol/mL), A. niger (0.0113 μmol/mL) and C. albicans (0.0056 μmol/mL) wherein triazolyl imidazoles 3i was found to be more potent against B. subtilis (0.0122 μmol/mL) & A. niger (0.0121 μmol/mL); and compound 3r was also found to be more potent against S. epidermidis (0.0117 μmol/mL) & C. albicans (0.0058 μmol/mL). As a result of docking studies, the binding affinity of the compound 3o was –9.6 kcal/mol which was even more in comparison to the binding affinity of co-crystallized ligand CBN (–9.4 kcal/mol).

Full text of DOI:10.1080/00397911.2019.1600192

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Synthesis, antimicrobial evaluation and docking
study of triazole containing triaryl-1H-imidazole
Sunil Chauhan, Vikas Verma, Devinder Kumar & Ashwani Kumar
To cite this article: Sunil Chauhan, Vikas Verma, Devinder Kumar & Ashwani Kumar (2019):
Synthesis, antimicrobial evaluation and docking study of triazole containing triaryl-1H-imidazole,
Synthetic Communications, DOI: 10.1080/00397911.2019.1600192
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https://doi.org/10.1080/00397911.2019.1600192
Synthesis, antimicrobial evaluation and docking study of
triazole containing triaryl-1H-imidazole
a
a
a
b
Sunil Chauhan , Vikas Verma , Devinder Kumar , and Ashwani Kumar
a
Department of Chemistry, Guru Jambheshwar University of Science & Technology, Hisar, India;
b
Department of Pharmaceutical Sciences, Guru Jambheshwar University of Science & Technology,
Hisar, India
ABSTRACT
ARTICLE HISTORY
An efficient route for the synthesis of triazole containing triaryl-1H-
imidazole (3a–3r) was achieved involving multicomponent conden-
sation of triazole aldehydes, ammonium acetate and 1,2-dicarbonyl
compounds in glacial acetic acid. The structure of newly synthesized
imidazoles was established by the FTIR, HRMS and NMR spectra. All
the compounds displayed considerable antimicrobial activity against
fungal and bacterial strains. The triazolyl imidazole 3p was substan-
tially potent against P. aeruginosa (0.0113 mmol/mL), A. niger
Received 17 September 2018
KEYWORDS
Antimicrobial activity;
docking simulation;
imidazole; multicomponent
synthesis; triazole
(
0.0113 mmol/mL) and C. albicans (0.0056 mmol/mL) wherein triazolyl
imidazoles 3i was found to be more potent against B. subtilis
0.0122 mmol/mL) & A. niger (0.0121 mmol/mL); and compound 3r was
(
also found to be more potent against S. epidermidis (0.0117 mmol/
mL) & C. albicans (0.0058 mmol/mL). As a result of docking studies,
the binding affinity of the compound 3o was –9.6 kcal/mol which
was even more in comparison to the binding affinity of co-crystal-
lized ligand CBN (–9.4 kcal/mol).
GRAPHICAL ABSTRACT
CONTACT Vikas Verma
vikas_chem_pu@yahoo.com
Department of Chemistry, Guru Jambheshwar University of
Science & Technology, Hisar, Haryana, 125001, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article is available online at on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
S. CHAUHAN ET AL.
Introduction
Among the variety of five membered-heterocyclic compounds, imidazole possesses
[
1]
[2]
[3]
widespread range of applications, effective biological activity and synthetic utility.
Many compounds having imidazole moiety play vital roles in biochemical processes
[
4]
and exhibits pharmacological properties. Imidazole derivatives demonstrate binding
[
5]
affinity with different metals, which are present in various biological active sites.
Imidazole derivatives display good inhibitory activity against tumor & bacteria,
inflammation, and show good pesticidal, cytotoxic and antioxidant activity.
[
6]
[
4]
[7]
[8]
[9,10]
Triazole is also a class of important N-heterocyclic molecules endowed with wide
spectrum of bioactivity and display antimicrobial, antiviral, antimalarial and anticancer
[
11–14]
activities.
This has attracted the chemist worldwide to design better therapeutic
molecules having different azole moieties so that combination of two scaffolds may
result in displaying more pharmacological activity. Therefore, we aimed to tether substi-
tuted traizoles with suitably functionalized imidazolyl scaffolds via aryloxy methylene
spacer to yield synergistic effect on antimicrobial and antifungal activities and their
docking study. The structure of these triazolyl imidazoles were established utilizing dif-
ferent spectral techniques (FTIR, 1D-NMR, 2D-NMR and HRMS) and evaluated for
antimicrobial activity against gram negative as well as gram positive and two fun-
gal strains.
Results and discussion
Chemistry
[
15]
The triazole substituted aryl aldehydes
(2a–2i) were obtained in good yield by react-
ing 4-(prop-2-yn-1-yloxy)benzaldehyde (1) with different organic azides in presence of
CuSO ꢀ5H O and sodium ascorbate using DMF:H O (7:3) as solvent at room tempera-
4
2
2
ture for 5–7 h. The resultant triazole aldehydes (2a–2i) were then reacted with 1,2-dicar-
bonyl compounds and ammonium acetate under reflux for 8–12 h thus generating
4
(
-((4-(4,5-diaryl-1H-imidazol-2-yl)phenoxy)methyl)-1-substituted-1H-1,2,3-triazole
3a–3r) in good yield (Scheme 1). All the synthesized compounds were characterized by
analyzing their FTIR, HRMS and NMR spectra.
1
The structure of compound 3a was identified by analyzing the FTIR, 1D-NMR ( H,
1
3C and DEPT-135), 2D-NMR (COSY, ROESY, HSQC, HMBC) and HRMS data. In
ꢁ
1
the FTIR spectrum, the band at 3614 cm was due to N–H stretching of imidazole ring
and the appearance of band at 3124 cm was assigned to C–H stretching of triazole
ring. In the H NMR spectrum of compound 3a, two singlets at d 5.29 ppm (2H) and
ꢁ
1
1
8
.86 ppm (1H) were assigned to CH O and C–H of triazole ring, respectively. A broad
2
singlet at d 12.70 ppm (1H) was established due to N–H of imidazole ring. The two
doublets at d 7.40 ppm and 7.76 ppm were attributed to C8 –H, C10 –H and C7 –H,
C11 –H, respectively. Similarly, another phenyl group attached with imidazole ring
0
0
0
0
showed two doublets at d 8.03 ppm and 7.18 ppm which were attributed to C –H,
8
C –H and C –H, C –H, respectively. A doublet of four protons at d 7.49 ppm was
1
0
7
11
endorsed to C –H, C –H and C –H, C –H, respectively. In 13C NMR spectrum of
1
3
17
19
23
3
a, peak at d 123.32 and 144.11 ppm were assigned for tertiary carbon and quaternary

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Scheme 1. Synthesis of triazole containing triaryl-1H-imidazole (3a–3r).
carbon of triazole ring, respectively and peak at d 133.23 ppm was due to quaternary
carbon of imidazole ring. In DEPT-135 spectrum of 3a, there appeared eight carbon sig-
nals for methine carbons, one carbon signal of methylene and another carbon signal of
methyl group.
The connectivity of all hydrogen atoms in 3a, through intervening bond was estab-
lished by COSY (Correlation Spectroscopy) and through space by ROESY (Rotational
1
1
Frame Overhauser Effect Spectroscopy) techniques. The H– H correlation between
vicinal protons of phenyl rings H8 /H10 with H7 /H11 and H /H with H /H , respect-
0
0
0
0
8
10
7
11
ively was corroborated through COSY spectrum. In ROESY spectrum, the hydrogen of
0
methylene (CH ) are found to be near to the hydrogen at position-5 of triazole ring
2
(Fig. 1).
The carbon-hydrogen correlations were established by analyzing the HSQC
(
Heteronuclear Single-Quantum Coherence) spectrum of 3a that revealed the position
0
of carbon signals at d 21.01 (CH ), 61.47 (OCH ), 115.46 (C-8, C-10), 120.56 (C-7 , C-
1
3
2
0
0
1 ), 123.32 (C-5 ), 123.53 (C-12, C-18), 127.42 (C-7, C-11), 127.71 (C-15, C-21), 128.25
0 0
C-14, C-16, C-20, C-22), 128.92 (C-13, C-17, C-19, C-23), 130.77 (C-8 , C-10 ), 133.23
(
(
0
0
0
C-2, C-4, C-5), 134.70 (C-9 ), 139.06 (C-6 ), 144.11 (C-1 ), 146.1 (C-6), 158.75

4
S. CHAUHAN ET AL.
1
13
Figure 1. H and C NMR of compound 3a.
(
7
8
C-9) ppm, because the key correlation was d 2.37!21.01, 5.29!61.47, 7.18!115.46,
.30!127.71, 7.36!128.21, 7.40!130.77, 7.49!128.92, 7.76!120.56, 8.03!127.42 and
.86!123.32 ppm.
Heteronuclear Multiple Bond Correlation (HMBC) experiment established the con-
nectivity of hydrogen with other carbons through multiple bond correlation of signals
at d 2.37–130.77 and 134.70, 7.40 to 21.01, 120.56 and 134.70, 5.29 to 123.32, 144.11
and 158.57 ppm. HMBC gives the information of carbon atom having two and three
0
bond coupling with hydrogens. Analysis of spectrum clearly indicated that proton 5 -H
0
0
attached with carbon C-5 showed two bond coupling with C-1 at d 144.11 ppm and
three-bond coupling with CH at d 61.47 ppm, respectively (Fig. 1). Mass spectrometry
2
also confirmed the structure of 3a by observing the molecular ion; HRMS (m/z) calcu-
þ
lated for C H N O: 483.2059. Found [M þ H] : 484.1923. All the other compounds
3
1
25 5
(
3b–3r) were similarly characterized.
Antimicrobial activity
The newly constructed 4-((4-(4,5-diaryl-1H-imidazol-2-yl)phenoxy)methyl)-1-substi-
tuted-1H-1,2,3-triazoles were monitored for in-vitro antibacterial activity against bacter-
ial strain (B. subtilis, S. epidermidis, E. coli, and P. aeruginosa) and also monitored for
antifungal activity against fungal strains (C. albicans and A. niger). Sabouraud dextrose
broth-I.P. and nutrient broth-I.P. were employed for fungal and bacterial growth,
respectively. Minimum Inhibitory Concentrations (MIC in mmol/mL) were scrutinized
[
12,13]
by serial dilution method
through a stock solution of 100 mg/mL and values in
mmol/mL are presented in Tables 1 and 2. The synthesized compounds exhibited con-
siderable activity against the used strains, where ciprofloxacin and fluconazole were
used as reference drugs in case of antibacterial and antifungal activities, respectively.
Antibacterial and antifungal activity
In general, the synthesized 4-((4-(4,5-diaryl-1H-imidazol-2-yl)phenoxy)methyl)-1-substi-
tuted-1H-1,2,3-triazoles displayed MIC value from 0.0513 to 0.0113 mmol/mL as com-
pared to reference drug ciprofloxacin (0.0047 mmol/mL) against antibacterial strains.
Among them, 3 h (0.0114 mmol/mL) and 3p (0.0113 mmol/mL) were substantially potent
against P. aeruginosa and 3o (0.0116 mmol/mL) showed promising activity against E.
coli. Compounds 3r (0.0117 mmol/mL) and 3i (0.0122 mmol/mL) were found to be more
potent against S. epidermidis and B. subtilis, respectively (Table 1). Most of the

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Table 1. In vitro antibacterial screening of compounds 3a–3r (MIC in mmol/mL).
Entry
Compounds
R
1
R
B. subtilis
S. epidermidis
E. coli
P. aeruginosa
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
H
4-CH
2-F
3
0.0259
0.0257
0.0250
0.0257
0.0248
0.0248
0.0242
0.0228
0.0122
0.0240
0.0478
0.0227
0.0239
0.0232
0.0232
0.0452
0.0214
0.0234
0.0047
0.0259
0.0257
0.0250
0.0513
0.0248
0.0497
0.0483
0.0457
0.0243
0.0240
0.0239
0.0227
0.0239
0.0232
0.0232
0.0226
0.0214
0.0117
0.0047
0.0259
0.0257
0.0250
0.0513
0.0248
0.0248
0.0241
0.0228
0.0243
0.0240
0.0239
0.0227
0.0239
0.0232
0.0116
0.0226
0.0429
0.0467
0.0047
0.0259
0.0257
0.0250
0.0513
0.0497
0.0248
0.0121
0.0114
0.0243
0.0120
0.0239
0.0227
0.0239
0.0232
0.0464
0.0113
0.0214
0.0234
0.0047
H
H
H
H
H
H
H
H
F
F
F
F
F
3
4-CH O
4-F
3-Cl
4-Cl
3
2-CH –3-Cl
4-Br
4-NO
2
4-CH
2-F
4-NO
4-F
3-Cl
4-Cl
10
11
12
13
14
15
16
17
18
19
3
2
F
F
F
F
2-CH
3
–3-Cl
3q
3r
4-Br
4-CH O
3
–
Ciprofloxacin
–
Table 2. In vitro antifungal screening of compounds 3a–3r (MIC in mmol/mL).
Entry
Compounds
R
1
R
A. niger
C. albicans
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
H
4-CH
2-F
3
0.0258
0.0257
0.0125
0.0128
0.0248
0.0248
0.0242
0.0114
0.0121
0.0481
0.0478
0.0227
0.0234
0.0116
0.0227
0.0113
0.0429
0.0233
0.0102
0.0129
0.0128
0.0063
0.0064
0.0062
0.0062
0.0060
0.0057
0.0243
0.0060
0.0060
0.0057
0.0060
0.0058
0.0058
0.0056
0.0107
0.0058
0.0051
H
H
H
H
H
H
H
H
F
F
F
F
F
3
4-CH O
4-F
3-Cl
4-Cl
3
2-CH –3-Cl
4-Br
4-NO
2
4-CH
2-F
4-NO
4-F
3-Cl
10
11
12
13
14
15
16
17
18
19
3
2
F
F
F
F
4-Cl
2-CH
3
–3-Cl
3q
3r
4-Br
4-CH O
3
–
Fluconazole
–
compounds with fluorine at R position were found to be more active against all the
1
bacterial strain and C. albicans. However, in compounds with fluorine at R position,
1
the presence of any substituents (R) at position-2 led to decrease in the activity against
B. subtilis whereas, the compound having methoxy substituent at position-4 was found
to possess increased activity against S. epidermidis. In case of gram negative bacteria 4-
Cl derivative showed maximum activity while 4-OCH and 4-Br derivative exhibited
3
minimum activity against E. coli. The methyl substitution (R) at position-4 led to high-
est activity of compound against P. aeruginosa.
The synthesized compounds showed good to moderate antifungal activity with MIC
value from 0.0481 to 0.0056 mmol/mL as compared to reference drug fluconazole against
A. niger (0.0102 mmol/mL) and C. albicans (0.0051 mmol/mL). All compounds were dis-
creetly active against the fungal species and compound 3p was observed to be more

6
S. CHAUHAN ET AL.
Figure 2. Interactions (dotted lines) of compound 3o docked in ligand binding region of DNA gyrase
topoisomerase II. (Green: hydrogen bond, Cyano: Halogen bond, Yellow: pi-anion, Light pink:
Hydrophobic interactions).
effective against A. niger (0.0113 mmol/mL) and C. albicans (0.0056 mmol/mL). All the
compounds except 3i showed better activity against C. albicans (0.0056–0.0243 mmol/
mL) than A. niger (0.0478–0.0113 mmol/mL), which are given in Table 2. It was also
observed that all triazole containing triaryl-1H-imidazole compounds (3a–3r) exhibited
[
16]
better antimicrobial activities as compared to 2a–2i.
Further, 3a–3r showed good
antifungal activity than 2a–2i against A. niger & C. albicans and almost comparable
antibacterial activity to 2a–2i.
Docking studies
The compound 3o was observed to be most active against E. coli. Therefore, it was
docked into the active site region of DNA gyrase of E. coli using Autodock Vina dock-
[
17]
ing tool.
The x-ray crystal structure of DNA gyrase was acquired from protein data
[
18]
bank (PDB: 1KZN) and the docking protocols were selected were adopted.
results were visualized with Discovery studio visualizer client 2017 R2.
The
[
19]
The lowest energy complex of compound 3o with the active site residues of DNA
gyrase is depicted in Fig. 2 that is anchored in the binding site by various types of inter-
actions. Interestingly, fluorine atoms played important role in affixing the molecule. The
fluorine atom present at position-4 of phenyl ring attached on imidazole made hydro-
[
20]
gen bonds
with Arg76 and Arg136 by behaving as acceptor. Further, both fluorine
[
21]
atoms created halogen bonds
with Glu50, Asp73, and Gly77. Glu42 built pi-anion
with chloro phenyl ring present on triazole. 4-Fluorophenyl rings made pi-
[
22]
contacts
anion contacts with Glu50. Imidazole and its substituent aromatic rings were involved
in hydrophobic interactions with the active site residues. Moreover, the binding affinity
of compound 3o was ꢁ9.6 kcal/mol which was more in comparison to the binding

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affinity of co-crystallized ligand CBN (–9.4 kcal/mol). These observations validated that
compound 3o efficiently inhibits the enzyme (Fig. 2).
Conclusion
In conclusion, 4-((4-(4,5-diaryl-1H-imidazol-2-yl)phenoxy)methyl)-1-substituted-1H-
1,2,3-triazoles (3a–3r) were synthesized from 1,2-dicarbonyl compounds and triazole
substituted aryl aldehydes in the presence of ammonium acetate in good yield. The syn-
thesized compounds were examined for in-vitro antimicrobial activity with serial dilu-
tion method that showed good to substantial antibacterial and antifungal activity. The
compound 3p was substantially more potent against P. aeruginosa, A. niger and C. albi-
cans, whereas compound 3i was more potent against B. subtilis and 3o and 3r were
more potent against E. coli & S. epidermidis. Docking simulation of compound 3o was
also carried out to study binding mode with drug target.
Experimental
The reagents and chemicals used were procured from Sigma-Aldrich and Himedia. The
reaction progress was monitored by TLC and melting points were determined in open
capillaries and are uncorrected. IR spectra were obtained in KBr on SHIMAZDU FTIR
1
spectrophotometer. H, 13 C, DEPT-135 and 2-D NMR (COSY, ROESY, HSQC and
HMBC) spectra were scanned on a Bruker Avance-III 400 MHZ FT-NMR. Chemical
shift values are reported in d (ppm) and coupling constant (J) value are given in Hertz
(Hz). HRMS were scanned on SCIEX (LC-MS/MS QTOF-5600þ).
Synthesis of 4-((4-(4,5-diphenyl-1H-imidazol-2-yl)phenoxy)methyl)-1-(p-tolyl)-1H-
1
,2,3-triazole (3a)
4-(Prop-2-yn-1-yloxy)benzaldehyde (1.0 mmol) was stirred with 4-methylphenylazide
(
1.0 mmol) in the presence of copper sulfate pentahydrate (0.10 mmol) and sodium
ꢂ
[14]
ascorbate (0.20 mmol) using DMF:water (7:3) as solvent at 40 C temperature for 8h.
After completion of the reaction, which was monitored through TLC, cold aq. NH3
solution was added to the reaction mixture and extracted thrice with ethyl acetate. The
ethyl acetate layer was dried using anhydrous Na SO , percolated and dried under vac-
2
4
uum to get 4-((1-(p-tolyl)-1H-1,2,3-triazol-4-yl)methoxy)benzaldehyde (2a) in 92% yield
that was crystallized from chloroform.
Compound 3a was synthesized by condensation of triazole substituted aryl aldehydes
(2a, 1.0 mmol) with benzil (1.0 mmol) and ammonium acetate (10.0 mmol) in glacial
acetic acid under reflux condition for 10 h. The reaction mixture was poured with stir-
ring into crushed ice with stirring. After 30 min, the precipitates were filtered, washed
twice with distilled water and dried under vacuum.
General procedure of antimicrobial activity
The newly synthesized 4-((4-(4,5-diphenyl-1H-imidazol-2-yl)phenoxy)methyl)-1-substi-
tuted-1H-1,2,3-triazoles were screened for in-vitro antibacterial activity against Bacillus

8
S. CHAUHAN ET AL.
subtilis MTCC 441, Staphylococcus epidermidis MTCC 6880 (Gram-positive) and
Escherichia coli MTCC 16521, pseudomonas aeruginosa MTCC 424 (Gram-negative) and
also screened for antifungal activity against fungal strains (Candida albicans MTCC 227
and Aspergillus niger MTCC 8189). Sabouraud dextrose broth-I.P. and nutrient broth-
I.P. were used for fungal and bacterial growth, respectively. Minimum Inhibitory
[
12,13]
Concentrations (MIC in mmol/mL) were examined by serial dilution method
using
a stock solution of 100 mg/mL. The synthesized compounds exhibited considerable activ-
ity against the used strains where ciprofloxacin and fluconazole were used as reference
drugs in case of antibacterial and antifungal activity, respectively. The stock solution of
control drug and synthesized compounds were diluted to different concentration of 50,
2
5, 12.5, 6.25, 3.12 mg/mL. All samples were prepared in dimethylsulfoxide and the
ꢂ
tubes-containing bacterial organism were incubated at 37 ± 0.5 C and the tubes contain-
ing fungal organism C. albicans were incubated at 30 ± 0.5 C for 48 h except in case of
ꢂ
A. niger which is incubated for 7 days and then compared with control drug.
Docking simulations
The procedure for docking simulation was followed according to the protocols reported
[
16,23]
by Kumar et al.
Sketch 5.10.
The 3D structure of the molecules was made using Marvin
[
24]
Additional Supporting information may be found online in the supporting informa-
tion tab for this article.
Funding
Authors are highly thankful to University Grant Commission, New Delhi, for financial assistance.
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[
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