Synthesis, antimicrobial activity, and QSAR studies of amide-ester linked 1,4-disubstituted 1,2,3-triazoles

Article abstract of DOI:10.1007/s00706-016-1766-y

Abstract: Synthesis of some amide-ester linked 1,4-disubstituted 1,2,3-triazoles was carried out by employing copper(I)-catalyzed 1,3-dipolar cycloaddition of 2-azido-N-substituted acetamides and benzoic acid prop-2-ynyl esters. All the synthesized 28 1,4-disubstituted 1,2,3-triazoles are new. The synthesized triazoles were characterized by IR, ¹H NMR, ¹³C NMR, HRMS and evaluated for their antimicrobial activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Candida albicans, and Aspergillus niger. Compounds displaying potent antimicrobial activity against each of these microorganisms were found. Quantitative structure activity relationship studies for the synthesized compounds were also carried out to check the effect of various substituents in parent compound on antimicrobial activity. Graphical abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00706-016-1766-y

Monatsh Chem
DOI 10.1007/s00706-016-1766-y
ORIGINAL PAPER
Synthesis, antimicrobial activity, and QSAR studies of amide-ester
linked 1,4-disubstituted 1,2,3-triazoles
1
1
2
•
C. P. Kaushik
Dharmendra Singh
•
Krishan Kumar
3
•
Balasubramanian Narasimhan
4
1
•
Pradeep Kumar
•
Ashima Pahwa
Received: 12 March 2016 / Accepted: 17 April 2016
Ó Springer-Verlag Wien 2016
Abstract Synthesis of some amide-ester linked 1,4-dis-
ubstituted 1,2,3-triazoles was carried out by employing
copper(I)-catalyzed 1,3-dipolar cycloaddition of 2-azido-
N-substituted acetamides and benzoic acid prop-2-ynyl
esters. All the synthesized 28 1,4-disubstituted 1,2,3-tria-
zoles are new. The synthesized triazoles were characterized
Graphical abstract
H
O
N
R
1
N
3
R
2
O
N
N
O
N
Click Reaction
O
Yield 60-98%
Twenty eight compounds
O
R
2
O
N
H
R
1
N
N
1
13
O
N
O
by IR, H NMR, C NMR, HRMS and evaluated for their
antimicrobial activity against Staphylococcus aureus,
Bacillus subtilis, Escherichia coli, Candida albicans, and
Aspergillus niger. Compounds displaying potent antimi-
crobial activity against each of these microorganisms were
found. Quantitative structure activity relationship studies
for the synthesized compounds were also carried out to
check the effect of various substituents in parent compound
on antimicrobial activity.
H
N
O
O
2
N
pMICbs and pMICca = 2.44 μM/cm
3
Keywords Heterocycles Á
1
,4-Disubstituted 1,2,3-triazoles Á Cycloaddition Á
Antibacterial Á Antifungal Á QSAR
Introduction
In the present scenario, the 1,2,3-triazoles have gained
much attention owing to their numerous applications in
various fields like pharmaceutical [1], agrochemical [2],
polymer [3], and material science [4]. 1,2,3-Triazole
derivatives possess diverse biological activities as antiviral
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-016-1766-y) contains supplementary
material, which is available to authorized users.
[
[
5], antimicrobial [6–11], antibiotic [12], antiprotozoal
13], antitubercular [14], anti-HIV [15], antimalarial [16],
&
C. P. Kaushik
kaushikcp@gmail.com
anticancer [17], and anti-inflammatory [18] agents. 1,3-
Dipolar cycloaddition reaction of organic azides to termi-
nal alkynes was first time scientifically studied by Huisgen
in twentieth century leading to the formation of 1,4- and
1,5-disubstituted 1,2,3-triazoles [19]. This area of research
was limited before Sharpless [20] and Meldal [21], who
independently discovered that the reaction of terminal
alkynes with organic azides using copper(I) as catalyst
leads to product in 1,4-regioselective fashion. This reaction
1
2
3
4
Department of Chemistry, Guru Jambheshwar University of
Science and Technology, Hisar, Haryana, India
Faculty of Pharmaceutical Sciences, Maharshi Dayanand
University, Rohtak, Haryana, India
Centre for Research and Development, IPCA Lab Ltd.,
Kandivali, Mumbai, Maharashtra, India
Centre for Pharmaceutical Sciences and Natural Products,
Central University of Punjab, Bathinda, India
123

C. P. Kaushik et al.
with salient features like higher yield, good selectivity,
simple reaction conditions, and versatile chemical trans-
formations, increased the interest of researchers and was
termed as one of the important click reaction. Moreover,
the use of click reaction have also been reported in the
literature for the construction of ionic receptors [22],
dendrimers [23], clusters [24], triazolophanes [25], gly-
copeptides [26], nanotubes [27], cyclic peptides [28],
peptidomimetics [29], and liquid crystals [30]. In the recent
years, quantitative structure activity relationship (QSAR)
has received importance in the field of medicinal chemistry
being a predictive tool for preliminary evaluation of the
activity of chemical compounds using computer-aided
models. QSAR techniques have increased the probability
of success with reduced time and low cost involvement in
drug discovery process [31]. So, keeping these views in
mind, we have used copper(I)-catalyzed click reaction to
synthesize a series of 1,4-disubstituted 1,2,3-triazoles 3a–
Scheme 1
H
Triethylamine
Dry DCM
Br
N
R1 NH2
Br
R1
Br
0
-15 ºC, 4-6 h
O
O
1
O
O
DMAP
Dry DCM
R2
Cl
R2
O
O
OH
0-10 °C, 2-4 h
2
H
O
N
1
Br
R2
N
N
R
NaN3
N
O
1
4 2
CuSO .5H O
Sodium ascorbate
O
DMF:H O (8:2)
2
O
5
0-60 ºC
R2
O
N
H
12-18 h
R1
2
3a-3z2
1
2
Compound
R
R
3a
C
6
C
6
C
6
C
6
H
H
H
H
5
5
5
5
-
-
-
-
p-CH
p-CH O-C
p-NO -C
p-F-C
p-CH -C
p-CH O-C
p-NO -C
p-F-C
p-CH -C
p-CH O-C
p-NO -C
p-F-C
p-CH -C
p-CH O-C
p-NO -C
p-F-C
p-CH -C
p-CH O-C
3 6 4
-C H -
3b
3
6
H
4
-
-
-
-
3c
2
6
H
4
-
3d
6 4
H -
3
z2 containing amide-ester linkages from benzoic acid
3e
p-CH
p-CH
p-CH
p-CH
3
3
3
3
-C
-C
-C
-C
6 4
H -
6 4
H -
6 4
H -
6 4
H -
3
6 4
H -
prop-2-ynyl esters and 2-azido-N-substituted acetamides
which were formed in situ by reaction of 2-bromo-N-sub-
stituted acetamides with sodium azide. All the synthesized
3f
3
6
H
4
3
g
h
2
6
H
4
-
3
6
4
H -
1
,4-disubstituted 1,2,3-triazoles are found to be new com-
3i
p-CH
p-CH
p-CH
p-CH
3
3
3
3
O-C
O-C
O-C
O-C
6 4
H -
6 4
H -
6 4
H -
6 4
H -
3
6 4
H -
pounds. The synthesized compounds were characterized by
13
3j
3
6
H
4
1
various spectroscopic techniques like IR, H NMR,
C
3k
2
6
H
4
-
3l
6 4
H -
NMR, HRMS and evaluated for their antibacterial and
antifungal activity. To observe the effect of various
molecular descriptors/parameters on antimicrobial activity,
QSAR studies of all synthesized compounds were also
carried out. QSAR models are mathematical equations
which construct a relationship between chemical structures
and their biological activities as a linear regression model
of the form y = Xb ? e. This equation may be used to
describe a set of predictor variables (X) with a predicted
variable (y) by means of a regression vector (b) [32].
3m
p-F-C
p-F-C
p-F-C
p-F-C
6
6
6
6
4
H -
4
H -
4
H -
4
H -
3
6 4
H -
3n
3o
3p
3q
3r
3
6
H
4
2
6
H
4
-
6
4
H -
p-Br-C
p-Br-C
6
4
H -
3
6 4
H -
6
4
H -
3
6 4
H -
3s
3t
p-Br-C H -
6
6
4
4
p-NO -C H -
2
6
4
p-Br-C
H
-
p-F-C
6
4
H -
3u
p-NO
p-NO
p-NO
p-NO
2
2
2
2
-C
-C
-C
-C
6 4
H
6 4
H
6 4
H
6 4
H
-
p-CH
p-CH
p-NO
p-F-C
p-CH -C
p-CH O-C
p-NO -C
p-F-C
3
-C
6 4
H -
3v
-
-
-
3
6
O-C H
4
-
3w
2
-C
H
6 4
-
3x
3y
3z
6 4
H -
α-Naphthyl
α-Naphthyl
α-Naphthyl
α-Naphthyl
3
6 4
H -
Results and discussion
Chemistry
3
6
H
4
-
3z
1
2
H
6 4
-
3z
2
6 4
H -
The synthetic strategy of the target compounds is given in
Scheme 1. 2-Bromo-N-substituted acetamides 1 were pre-
pared reacting various aromatic amines with bromoacetyl
bromide in dry dichloromethane at 0–15 °C using triethy-
lamine as base, while benzoic acid prop-2-ynyl esters 2
were synthesized by reacting corresponding benzoyl chlo-
rides with propargyl alcohol in dry dichloromethane at
prop-2-ynyl esters 2 in dimethylformamide:water in the
presence of sodium azide, copper sulfate pentahydrate and
sodium ascorbate with stirring of 12–18 h at 50–60 °C
(Scheme 1). The synthesized triazole compounds were
1
13
0
–10 °C in the presence of N,N-dimethylaminopyridine.
characterized by IR, H NMR, C NMR, and high reso-
lution mass spectrometry. The formation of triazole
compounds were confirmed by the presence of absorption
Finally, 1,4-disubstituted 1,2,3-triazoles 3a–3z containing
amide-ester linkages were synthesized by reacting
2
-
1
2
-bromo-N-substituted acetamides 1 and benzoic acid
bands in the region at 3304–3217 cm (N–H str., amide),
1
23

Synthesis, antimicrobial activity, and QSAR studies of amide-ester linked 1,4-disubstituted…
3
Table 1 Antimicrobial activity data (pMIC in lM/cm ) of synthesized compounds 3a–3z
2
Compound
pMICsa
pMICbs
pMICec
pMICca
pMICan
pMICab
pMICaf
pMICam
a
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
1.45
1.47
2.09
1.45
1.16
1.48
2.10
2.07
1.48
1.50
1.52
1.49
2.37
1.49
1.50
2.38
1.54
1.55
1.27
1.54
1.50
2.12
1.53
2.11
1.51
1.52
1.54
1.51
2.61
–
1.45
1.47
2.09
1.45
2.07
1.48
1.50
1.47
1.48
1.50
2.42
1.49
1.47
1.49
1.50
1.47
2.14
1.55
1.57
1.54
1.50
2.42
1.53
1.50
1.51
1.52
2.44
1.51
2.61
–
1.45
2.07
1.48
1.45
1.46
2.39
1.50
1.47
1.48
2.10
1.52
1.49
1.47
1.49
1.50
1.47
1.54
1.55
2.17
1.54
1.50
1.52
1.53
1.50
2.41
1.22
1.54
1.51
2.61
–
1.45
1.47
1.48
2.05
2.37
1.48
1.50
1.47
1.48
1.50
2.12
1.49
1.47
1.19
2.11
1.47
1.54
1.55
1.57
2.44
1.50
1.52
1.53
2.41
1.51
1.52
2.44
1.51
–
1.45
1.47
1.48
2.36
1.46
1.48
1.50
2.37
1.48
1.50
1.52
1.49
1.47
1.49
1.50
1.47
2.14
1.55
1.57
1.54
1.50
1.52
1.53
2.11
1.51
1.52
1.54
1.51
–
1.45
1.45
1.47
1.45
1.59
1.73
1.75
1.71
1.66
1.62
1.77
1.48
1.62
1.82
1.49
1.65
1.43
1.62
1.65
1.78
1.55
1.63
1.72
1.50
1.82
1.53
1.93
1.69
1.46
1.90
1.51
–
1.67
a
b
1.89
1.48
a
1.45
1.57
1.78
1.70
2.21
a
1.92
1.48
1.50
g
h
i
b
a
1.67
1.92
b
1.48
1.48
1.50
j
1.70
a
b
k
l
1.82
1.82
1.49
1.77
1.49
1.47
m
n
o
p
q
r
s
b
a
1.49
1.34
b
1.50
1.81
a
1.78
1.47
b
1.74
1.55
1.67
1.54
1.84
1.55
1.57
a
t
1.99
a
u
v
w
x
y
z
1.50
1.50
1.52
1.53
a
2.02
1.53
1.71
a
2.26
b
1.81
1.51
1.52
a
1.42
a
z
z
1
2
1.84
1.99
b
1.51
1.51
–
Norfloxacin
Fluconazole
SD
–
2.64
0.36
3
2.64
0.27
–
–
–
0.33
0.33
0.30
0.16
0.25
0.14
pMICsa, pMICbs, pMICec, pMICca and pMICan = -log MIC in lM/cm against different microorganisms. i.e. Staphylococcus aureus, Bacillus
subtilis, Escherichia coli, Candida albicans and Aspergillus niger, respectively
SD means standard deviation
a
b
Test set; outliers
-
-
1
1
3
170–3120 cm
(C–H,
str.,
triazole
ring),
-1
Antibacterial activity
1
722–1691 cm (C=O str., ester), and 1699–1656 cm
(
C=O str., amide) in IR spectra. The presence of charac-
teristic singlet in the region at d = 5.32–5.52 (OCH2),
.40–5.60 (NCH ), 8.26–8.38 (CH triazole), 10.35–11.12
All the synthesized 1,4-disubstituted 1,2,3-triazoles 3a–3z
2
were screened for in vitro antibacterial activity against
Staphylococcus aureus (MTCC 1430), Bacillus subtilis
(MTCC 2423), and Escherichia coli (MTCC 739). The
antibacterial potency of the compounds was compared with
standard drug, norfloxacin. The minimum inhibitory con-
centration (MIC) values are given in Table 1.
5
2
1
(
NH amide) ppm in H NMR spectra and peaks in the
region at d = 52.6–52.8 (NCH ), 58.1–59.7 (OCH ),
1
2
2
27.0–127.4 (C-5 triazole ring), 141.6–142.3 (C-4 triazole
ring), 164.1–164.9 (C=O ester), 165.0–165.9 (C=O amide)
1
3
ppm in C NMR spectra also confirmed the formation of
target compounds. The results obtained from high resolu-
tion mass spectral analysis were found in accordance to the
calculated values.
The results obtained from antibacterial studies revealed
that the compounds 3a–3z showed moderate to good
2
activities against tested bacterial strains. Compounds 3m
3
and 3p (pMICsa = 2.37 and 2.38 lM/cm , respectively)
123

C. P. Kaushik et al.
were found to possess good potential against S. aureus,
electron withdrawing group like nitro on amino phenyl
moiety also appeared as potent antibacterial agent
against B. subtilis.
whereas, compounds 3k, 3v, and 3z (pMICbs = 2.42,
1
3
2
.42, and 2.44 lM/cm , respectively) displayed better
activity against B. subtilis. In case of E. coli, compounds 3f
3. Presence of electron donating groups on benzoate
moiety improved the antibacterial activity against
E. coli in the triazoles having phenyl (3b), toluyl (3f),
p-methoxyphenyl (3j), and naphthyl (3y) moieties
linked at nitrogen atom of amide bond. However,
compound 3s possessing electron withdrawing group on
benzoate moiety with bromo at amino phenyl moiety
also proved as good antibacterial agents against E. coli.
3
and 3y (pMICec = 2.39 and 2.41 lM/cm , respectively)
emerged as potent antibacterial agents.
Antifungal activity
The in vitro antifungal activity of the 1,4-disubstituted
1
,2,3-triazoles 3a–3z were examined against two fungal
2
1
strains viz. Candida albicans (MTCC 854) and Aspergillus
niger (MTCC 282). Fluconazole was used as standard drug.
The MIC values of the synthesized triazoles and the stan-
dard drug are furnished in Table 1.
4. The triazoles having p-flourobenzoate moiety with R
representing phenyl (3d), p-bromophenyl (3t), and p-
nitrophenyl (3x) exhibited better antifungal potency
against C. albicans; compounds having electron with-
drawing group, i.e., nitro on benzoate moiety with p-
methoxyphenyl (3k), p-flourophenyl (3o), and naphthyl
Antifungal activity results indicated that most of the
synthesized compounds exhibited moderate to good activ-
ities against tested fungal strains. Compounds 3e, 3t, 3x,
(3z ) groups on nitrogen of amide bond appeared as
1
3
and 3z (pMIC = 2.37, 2.44, 2.41, and 2.44 lM/cm ,
potent fungicidal agents. Furthermore, compound 3e
containing electron donating group, i.e., methyl on both
1
ca
respectively) displayed remarkable antifungal activity
against C. albicans; compounds 3d and 3h (pMIC = 2.36
an
3
and 2.37 lM/cm , respectively) appeared as potential
antifungal agents against A. niger.
Table 2 QSAR descriptors used in the study
In general, antimicrobial activity results reflected that
the compound 3z as a potent antimicrobial agent (pMIC
S.
no.
QSAR descriptor
Type
1
bs
3
and pMICca = 2.44 lM/cm ), having antimicrobial effi-
cacy comparable to standard drugs, norfloxacin
1
2
3
4
5
log P
Lipophilic
3
(
(
pMIC = 2.61 lM/cm )
pMIC = 2.64 lM/cm ), respectively.
and
fluconazole
0
Zero order molecular connectivity index ( v)
Topological
Topological
3
1
First order molecular connectivity index ( v)
2
Second order molecular connectivity index ( v) Topological
Structure activity relationship studies
Valence zero order molecular connectivity index Topological
0
v
v )
(
From the above antimicrobial activity results, the following
structure activity relationship can be drawn:
6
7
Valence first order molecular connectivity index Topological
1
v
( v )
Valence second order molecular connectivity
2 v
index ( v )
Topological
1
. Presence of electron withdrawing groups, i.e., nitro on
benzoate moiety in triazoles containing either phenyl
8
9
Kier’s alpha first order shape index (ja
1
)
Topological
Topological
Topological
Topological
Topological
Topological
Topological
Electronic
(
3c) or toluyl (3g) groups at nitrogen atom of amide
2
Kier’s alpha second order shape index (ja )
linkage improved the antibacterial activity against S.
aureus; the presence of methoxy (3v) and flouro (3x)
groups on benzoate moiety in the compounds having p-
nitrophenyl at nitrogen of amide bond also increased the
bactericidal activity. Moreover, the triazoles containing
methyl (3m) and fluoro (3p) groups on benzoate moiety
with p-fluorophenyl at nitrogen of amide bond also
displayed good antibacterial efficiency against S.
aureus.
10
11
12
13
14
15
16
17
Kier’s first order shape index (j
1
)
Randic topological index
Balaban topological index
Wiener’s topological index
Kier’s second order shape index (j
Ionization potential
2
)
Dipole moment (l)
Electronic
Energy of highest occupied molecular orbital
HOMO)
Energy of lowest unoccupied molecular orbital Electronic
LUMO)
Electronic
(
2
. Triazoles with electron withdrawing group, i.e., nitro on
benzoate moiety containing phenyl (3c), p-methoxy-
phenyl (3k), and naphthyl (3z ) groups on nitrogen atom
1
8
(
1
19
Total energy (Te)
Electronic
Electronic
Steric
of amide linkage exhibited potent antibacterial activity
against B. subtilis; compound (3v) containing electron
donating group, i.e., methoxy on benzoate moiety and
2
2
0
1
Nuclear energy (Nu. E)
Molar refractivity (MR)
1
23

Synthesis, antimicrobial activity, and QSAR studies of amide-ester linked 1,4-disubstituted…
Table 3 Values of selected descriptors used in the present study
0
v
0 v
v
Compound
log P
MR
R
Te
HOMO
l
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
3.15
2.43
2.63
2.82
3.61
2.89
3.10
3.29
2.89
2.17
2.38
2.57
3.29
2.57
2.77
2.96
3.94
3.22
3.43
3.61
3.10
2.38
2.59
2.77
4.15
3.43
3.64
3.82
97.90
18.36
19.06
19.93
18.36
19.23
19.93
20.80
19.23
19.93
20.64
21.51
19.93
19.23
19.93
20.80
19.23
19.23
19.93
20.80
19.23
20.80
21.51
22.38
20.80
20.92
21.63
22.50
20.92
14.25
14.66
14.52
13.63
15.18
15.59
15.44
14.55
15.59
15.99
15.85
14.96
14.55
14.96
14.82
13.93
16.18
16.59
16.44
15.55
15.44
15.85
15.70
14.82
16.41
16.82
16.67
15.79
12.60
13.14
13.51
12.60
12.99
13.53
13.90
12.99
13.53
14.07
14.44
13.53
12.99
13.53
13.90
12.99
12.99
13.53
13.90
12.99
13.90
14.44
14.81
13.90
14.58
15.12
15.49
14.58
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-4942.12
-5262.14
-5617.01
-5257.65
-4937.68
-5257.70
-5612.57
-5253.21
-4805.89
-5125.91
-5480.78
-5121.41
-5297.17
-5617.18
-5972.05
-5612.69
-5005.51
-5325.51
-5680.40
-5321.03
-8.96
-8.97
-9.08
-9.03
-8.76
-8.78
-8.88
-8.82
-8.57
-8.57
-8.67
-8.61
-8.95
-8.97
-9.07
-9.00
-9.05
-9.05
-9.15
-9.07
-9.77
-9.64
-9.88
-9.79
-8.94
-8.98
-9.07
-9.00
4.29
99.32
100.18
93.07
4.43
4.18
1.45
3.94
4.09
4.43
1.91
4.12
4.35
3.51
1.90
5.80
5.16
3.33
3.39
5.36
5.33
3.53
3.08
10.14
9.65
4.67
7.81
5.70
6.96
8.94
6.23
102.94
104.36
105.22
98.11
g
h
i
104.36
105.78
106.64
99.53
j
k
l
m
n
o
p
q
r
s
98.11
99.53
100.40
93.29
105.52
106.94
107.80
100.69
105.22
106.64
107.50
100.40
114.35
115.77
116.63
109.52
t
u
v
w
x
y
z
z
z
1
2
benzoate and amino phenyl moieties displayed good
transformed into pMIC values (i.e. -log MIC) and used as
dependent variables in QSAR study as given in Table 1.
The different molecular descriptors selected for the present
study are listed in Table 2.
fungicidal action against C. albicans.
5
. The triazoles possessing flouro group on benzoate
1
moiety with R representing phenyl (3d), p-toluyl
3h), p-nitrophenyl (3x) appeared as effective antifun-
(
Molecular descriptors (independent variables) like log
of octanol–water partition coefficient (log P), molar
gals against A. niger; compound 3q containing electron
donating group on benzoate moiety with bromo on
amino phenyl moiety also appeared as good antifungal
agent against A. niger.
0
0 v
refractivity (MR), Kier’s molecular connectivity ( v, v ,
1
1 v
2
2 v
v, v , v, v ) and shape (j , ja , ja , ja ), topological
1
1
2
3
indices, Randic topological index (R), Balaban topological
index (J), Wiener topological index (W), total energy (Te),
energies of highest occupied molecular orbital (HOMO)
and lowest unoccupied molecular orbital (LUMO), dipole
moment (l) and electronic energy (Ele. E) were calculated
for the synthesized triazoles 3a–3z2 and the values of
selected descriptors are presented in Table 3.
QSAR studies
Quantitative structure activity relationship (QSAR) is a
predictive tool for preliminary evaluation of the activity of
compounds through computer-aided models. To identify
the substituent effect on the antimicrobial activity, QSAR
studies were undertaken, by employing the linear free
energy relationship (LFER) model [33]. The biological
activity data determined as MIC values were first
Our previous studies in the field of QSAR [32, 34]
indicated that the multi-target QSAR (mt-QSAR) models are
better than one target QSAR (ot-QSAR) models in
describing the antimicrobial activity. According to the ot-
123

C. P. Kaushik et al.
QSAR models, a person should apply five different equa-
tions with different errors to predict the activity of a new
compound against five microbial species. The application of
ot-QSAR models, which are generally seen in the whole
literature, however, were not practical when we had to
predict each compound results for more than one target. In
those cases we had to develop one ot-QSAR for each target.
However, very recently the interest has been increased
in the development of multi-target QSAR (mt-QSAR)
models. As opposed to ot-QSAR, the mt-QSAR model is a
single equation that considers the nature of molecular
descriptors which are common and essential for describing
the antibacterial and antifungal activity [35–38].
2. X Outliers are substances whose molecular descriptors
do not lie in the same range as the (rest of the) training
data.
3. Y Outliers are only defined for training or test samples.
They are substances for which the reference value of
response is invalid.
As there was no difference in the activity (Table 1) as
well as the molecular descriptor range (Table 3) of these
outliers when compared to other synthesized 1,4-disubsti-
tuted 1,2,3-triazoles indicated the fact that these outliers
belong to the category of Y outliers (substances for which
the reference value of response is invalid).
The average antifungal activity values were correlated
with the molecular descriptors of synthesized compounds
In this study, we attempted to develop two types of mt-
QSAR models viz. mt-QSAR model for describing
antibacterial activity of synthesized compounds 3a–3z2
against S. aureus, B. subtilis, and E. coli as well as mt-
QSAR model for describing antifungal activity of synthe-
sized compounds against C. albicans and A. niger by
calculating their average antibacterial and antifungal
activity values which are presented in Table 1. The stan-
dard drugs norfloxacin and fluconazole were not included
in model generation because of dissimilarity in structure
with synthesized compounds.
(Table 4). In general, high colinearity (r [ 0.5) was
observed between different parameters. The high inter-
relationship was observed between topological
0
parameters, zero order molecular connectivity index ( v)
and Randic index (R) (r = 0.946), and low interrela-
tionship was observed between electronic parameter,
energy of highest occupied molecular orbital (HOMO)
and lipophilic parameter, log P (r = 0.039). Correlation
matrix for antibacterial activity of synthesized com-
pounds with their molecular descriptors is given in
Table 5.
The data set of 28 triazoles 3a–3z was divided into
2
training set and test sets. Different compounds were taken
From the correlation matrix (Table 4), it was observed
that topological parameter, valance zero order molecular
in the test set on random selection basis. Compounds 3a,
3
c, 3k, 3p, 3u, 3v, and 3z were taken in test set for
antibacterial activity whereas compounds 3d, 3e, 3h, 3n,
t, 3x, and 3z were taken in test set for antifungal activity.
0
v
connectivity index ( v ) was found to be dominating
descriptor for antifungal activity of the synthesized
compounds (Eq. 1).
3
1
Different outliers were identified in case of antibacterial
3h, 3i, 3n, 3y, and 3z ) and antifungal (3c, 3k, 3o, and 3q)
(
2
MLR-mt-QSAR model for antifungal activity
activities and the QSAR models have been developed after
removal of these outliers. In multivariate statistics, it is
common to define three types of outliers [39].
0
v
À5
pMIC ¼ 0:024 v À3:71 Â 10 Te þ 0:934
af
2
n ¼ 17; r ¼ 0:896; q ¼ 0:715; s ¼ 0:015; F ¼ 28:49
1
. X/Y Relation outliers are substances for which the
relationship between the descriptors (X variables) and
the dependent variables (Y variables) is not the same as
in the (rest of the) training data.
ð1Þ
Here and thereafter, n number of data points, r correlation
2
coefficient, q cross validated r obtained by leave one out
2
Table 4 Correlation matrix for antifungal activity of synthesized compounds
0
v
0 v
v
pMICaf
log P
MR
R
Te
HOMO
l
pMICaf
log P
MR
1.000
0.213
1.000
0.442
0.058
0.298
0.209
0.173
0.039
0.129
0.666
1.000
0
v
0.694
0.771
0.926
1.000
0
v
v
0.815
0.707
0.946
1.000
0.768
R
0.629
0.881
1.000
Te
-0.676
-0.376
0.185
-0.383
-0.175
0.394
-0.856
-0.515
0.413
-0.415
-0.101
0.287
-0.699
-0.356
0.414
1.000
HOMO
0.588
1.000
l
-0.233
-0.641
1.000
1
23

Synthesis, antimicrobial activity, and QSAR studies of amide-ester linked 1,4-disubstituted…
Table 5 Correlation matrix for antibacterial activity of synthesized compounds
0
v
0 v
v
pMICab
log P
MR
R
Te
HOMO
l
pMICab
log P
MR
1.000
0.259
0.506
0.260
0.399
0.321
-0.006
0.063
0.730
1.000
0.328
-0.117
0.395
1.000
0
v
0.751
0.904
1.000
0
v
v
0.532
0.978
1.000
0.549
R
-0.128
0.230
0.790
1.000
Te
-0.480
-0.104
0.598
-0.907
-0.443
0.518
-0.331
-0.009
0.430
-0.847
-0.345
0.561
1.000
HOMO
-0.001
0.267
0.597
1.000
l
-0.344
-0.392
1.000
method, s standard error of the estimate, and F Fischer
statistics.
expressing antibacterial activity of the synthesized com-
pounds. So, QSAR model for antibacterial activity (Eq. 2)
was developed using l.
The developed QSAR model for antifungal activity
(
Eq. 1) indicated that there is a positive correlation
0
v
between v and antifungal activity of the synthesized
compounds. Hence, antifungal activities of synthesized
MLR-mt-QSAR model for antibacterial activity
0
v
compounds will increase with increase in their v values
Tables 1 and 3). In case of Te, the antifungal activity of
(
pMICab ¼ 0:139 HOMO þ 0:056l þ 2:65
synthesized compounds will decrease with increase in their
Te values as its coefficient is negative.
2
n ¼ 16; r ¼ 0:822; q ¼ 0:580; s ¼ 0:073; F ¼ 13:59
ð2Þ
The molecular connectivity index, an adjacency based
topological index proposed by Randic is denoted by v and
is defined as sum over all the edges (ij) as per following:
n
Antibacterial activity of the synthesized compounds is also
positively correlated with their l and HOMO values which
mean that antibacterial activity of the synthesized com-
pounds will increase with increase in their l and HOMO
values (Tables 1, 3).
XÀ
ÁÀ1=2
v ¼
ViVj
i¼1
where V and V are the degrees of adjacent vertices i and
The importance of dipole moment in modulating
antibacterial activity of 1,4-disubstituted 1,2,3-triazole
bacterial targets may be due to the presence of carbonyl
group (Cd?=Od-) where permanent polarization is seen
due to electronegativity difference between the atoms. This
permanent polarization may results in a dipole–dipole
interaction with antibacterial target [43].
i
j
j and n is the number of vertices in a hydrogen suppressed
molecular structure [40]. The topological index, v signifies
the degree of branching, connectivity of atoms and unsat-
uration in the molecule which accounts for variation in
activity [41]. In QSAR, the total energy plays important
role. Total energy of a molecular system is the sum of the
total electronic energy, and the energy of internuclear
repulsion [41].
According to the FMO concept, the HOMO and LUMO
of a molecule play important roles in intermolecular
interactions. Extending the concept to binding in drug-re-
ceptor systems, the major contribution to binding involves
the interaction between the HOMO of the drug with the
LUMO of the receptor and that between LUMO of the drug
with the HOMO of the receptor. The extents of these sta-
bilizing interactions are inversely related to the energy gap
between the interacting orbitals [44].
The developed QSAR model (Eq. 1) was cross vali-
2
dated by q value (q = 0.715) obtained by leave one
2
2
out (LOO) method. The value of q more than 0.5
indicated that the model developed is a valid one.
According to the recommendations of Golbraikh and
Tropsha, the only way to estimate the true predictive
power of a model is to test their ability to predict
accurately the biological activities of compounds. As the
observed and predicted values are close to each other
The validity of QSAR model for antibacterial activity
2
(Eq. 2) is indicated by its high q value (0.580) as well as
(
(
Table 6), the mt-QSAR model for antifungal activity
Eq. 1) is a valid one [42].
the low residual values (Table 6). The developed models
(Eqs. 1, 2) were also able to predict the activity of test sets.
The high residual values observed in case of outliers jus-
tified their removal while developing QSAR models.
In case of antibacterial activity, electronic parameter,
dipole moment (l, Table 5) was found most dominant in
123

C. P. Kaushik et al.
Table 6 Observed, predicted and residual antibacterial and antifungal activities of the synthesized compounds obtained by developed QSAR
models (Eqs. 1, 2)
Compound
pMICab
Obs.
pMICaf
Obs.
Pre.
Res.
0.01
Pre.
Res.
0.01
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
1.45
1.67
1.89
1.45
1.57
1.78
1.70
1.67
1.48
1.70
1.82
1.49
1.77
1.49
1.50
1.78
1.74
1.55
1.67
1.54
1.50
2.02
1.53
1.71
1.81
1.42
1.84
1.51
1.44
1.46
1.47
1.44
1.47
1.49
1.50
1.47
1.49
1.51
1.52
1.49
1.47
1.49
1.50
1.46
1.50
1.52
1.53
1.50
1.50
1.52
1.53
1.50
1.51
1.54
1.54
1.51
1.45
1.47
1.48
2.21
1.92
1.48
1.50
1.92
1.48
1.50
1.82
1.49
1.47
1.34
1.81
1.47
1.84
1.55
1.57
1.99
1.50
1.52
1.53
2.26
1.51
1.52
1.99
1.51
1.44
1.46
1.47
1.44
1.47
1.49
1.50
1.47
1.49
1.51
1.52
1.49
1.47
1.49
1.50
1.46
1.50
1.52
1.53
1.50
1.50
1.52
1.53
1.50
1.51
1.54
1.54
1.51
0.21
0.42
0.01
0.10
0.29
0.20
0.20
-0.01
0.19
0.30
0.00
0.30
0.00
0.00
0.32
0.24
0.03
0.14
0.04
0.00
0.50
0.00
0.21
0.30
-0.12
0.30
0.00
0.01
0.01
0.77
0.45
-0.01
0.00
0.45
-0.01
-0.01
0.30
0.00
0.00
-0.15
0.31
0.01
0.34
0.03
0.04
0.49
0.00
0.00
0.00
0.76
0.00
-0.02
0.45
0.00
g
h
i
j
k
l
m
n
o
p
q
r
s
t
u
v
w
x
y
z
z
z
1
2
It was observed from mt-QSAR models (Eqs. 1, 2) that
the antibacterial and antifungal activities of the synthesized
,4-disubstituted 1,2,3-triazoles were governed by elec-
The minimum standard deviation (Table 1) observed in
the antimicrobial activity data justifies its use in QSAR
studies.
1
tronic parameter, dipole moment (l) and topological
parameter, valence zero order molecular connectivity index
0
v
(
v ), respectively.
Generally for QSAR studies, the biological activities
Conclusion
of compounds should span 2–3 orders of magnitude.
But in this study the range of antimicrobial activities of
the synthesized compounds is within one order of
magnitude. This is in accordance with results suggested
by Bajaj et al. [45] who stated that the reliability of the
QSAR model lies in its predictive ability even though
the activity data are in the narrow range. When bio-
logical activity data lies in the narrow range, the
presence of minimum standard deviation of the bio-
logical activity justifies its use in QSAR studies [46].
A series of amide-ester linked 1,4-disubstituted 1,2,3-tria-
zoles 3a–3z2 was synthesized through an easy Cu(I)-
catalyzed click reaction of 2-azido-N-substituted acet-
amides with benzoic acid prop-2-ynyl esters and evaluated
for their in vitro antimicrobial activity against S. aureus, B.
subtilis, E. coli, C. albicans, and A. niger. Compounds 3m,
3p against S. aureus, compounds 3k, 3v, 3z against B.
1
subtilis, and compounds 3f, 3y against E. coli showed
antibacterial activity comparable to standard drug, nor-
floxacin. The compounds 3e, 3t, 3x, 3z against C. albicans
1
1
23

Synthesis, antimicrobial activity, and QSAR studies of amide-ester linked 1,4-disubstituted…
and compounds 3d, 3h against A. niger displayed potent
antifungal activity like reference drug, fluconazole.
Remaining synthesized triazole compounds have moderate
to good antimicrobial activity. The QSAR studies were
carried out to predict the relationship between various
physicochemical parameters and antimicrobial activity of
of the reaction, ice cold water was added to the reaction
mixture, then filtered the precipitated solid and washed
with aqueous ammonia solution followed by water. To
remove traces of reactants and other impurities, crude
product was washed with ethyl acetate, dried under vacuum
to afford the desired 1,4-disubstituted 1,2,3-triazoles 3a–
1
,4-disubstituted 1,2,3-triazoles 3a–3z which indicated the
2
3z
1-[2-Oxo-2-(phenylamino)ethyl]-1H-1,2,3-triazol-4-
yl]methyl 4-methylbenzoate (3a, C H N O )
2
in good yields.
importance of dipole moment (l) and zero order molecular
[
0
v
connectivity index ( v ) in describing the antibacterial and
antifungal activities of the synthesized compounds,
respectively.
1
9 18 4 3
1
Light yellow solid; yield: 81 %; m.p.: 206–210 °C; H
NMR (400 MHz, DMSO-d ): d = 2.38 (s, 3H, CH ), 5.37
6
3
(s, 2H, OCH ), 5.42 (s, 2H, NCH ), 7.09 (t, J = 8.0 Hz,
2 2
1
H, Ar–H), 7.32–7.35 (m, 4H, Ar–H), 7.59 (d, J = 8.0 Hz,
H, Ar–H), 7.87 (d, J = 8.0 Hz, 2H, Ar–H), 8.29 (s, 1H,
Experimental
2
1
C–H triazole), 10.49 (s, 1H, N–H amide) ppm; C NMR
3
All the chemicals were purchased from commercial sup-
pliers and used without further purification. Melting points
of the target compounds were recorded in °C by applying
open capillary method and are corrected. The IR spectra
were recorded on Shimazdu IR Affinity-I FT-IR spec-
trophotometer using potassium bromide powder and values
(
100 MHz, DMSO-d ): d = 21.6, 52.7, 58.2, 119.7, 124.2,
27.1 (C-5 triazole), 129.4, 129.8, 138.9, 142.2 (C-4
6
1
triazole), 144.3, 164.6 (C=O ester), 165.9 (C=O amide)
ppm; FT-IR (KBr): v = 3257 (N–H str., amide), 3143 (C–
H str., triazole ring), 3066, 1712 (C=O str., ester), 1672
-
1
(
C=O str., amide), 1605, 1550, 1444, 1282, 1105 cm ;
-
1
1
are given in cm . The H NMR spectra were recorded on
?
HRMS: m/z for C H N O 349.13126 ([M?H] ).
1
3
19 18 4 3
Bruker Avance II 400 MHz spectrometer and C NMR on
Bruker Avance II 400 at 100 MHz, in deuterated
dimethylsulfoxide using tetramethylsilane (TMS) as an
internal standard (chemical shift in d, ppm). Coupling
constant (J) values are given in Hertz (Hz). High resolution
mass spectra were recorded on Waters Micromass Q-Tof
Micro (ESI) spectrometer. The completion of reactions and
the purity of the compounds were analyzed by thin layer
chromatography (TLC) using readymade silica gel plates
[1-[2-Oxo-2-(phenylamino)ethyl]-1H-1,2,3-triazol-4-
yl]methyl 4-methoxybenzoate (3b, C19
White solid; yield: 75 %; m.p.: 176–180 °C; H NMR
(400 MHz, DMSO-d ): d = 3.83 (s, 3H, OCH ), 5.34 (s,
2H, OCH ), 5.44 (s, 2H, NCH ), 7.05 (d, J = 8.0 Hz, 2H,
H N O )
18 4 4
1
6
3
2
2
Ar–H), 7.09 (t, J = 8.0 Hz, 1H, Ar–H), 7.34 (d,
J = 8.0 Hz, 2H, Ar–H), 7.59 (d, J = 8.0 Hz, 2H, Ar–H),
7.93 (d, J = 8.0 Hz, 2H, Ar–H), 8.26 (s, 1H, C–H triazole),
1
3
(
SIL G/UV254, ALUGRAM) and visualized under ultra-
10.50 (s, 1H, N–H amide) ppm; C NMR (100 MHz,
DMSO-d ): d = 52.7, 56.0, 58.1, 114.6, 119.7, 122.0,
24.2, 127.0 (C-5 triazole), 129.4, 131.8, 138.9, 142.3 (C-4
violet lamp.
6
1
General procedure for the synthesis of 1,4-disubstituted
triazole), 163.8, 164.3 (C=O ester), 165.9 (C=O amide)
ppm; FT-IR (KBr): v = 3278 (N–H str., amide), 3134 (C–
H str., triazole ring), 3068, 1707 (C=O str., ester), 1668
1
,2,3-triazoles 3a–3z2
-Bromo-N-substituted acetamides 1 were synthesized by
2
drop-wise addition of bromoacetyl bromides (1.2 mmol) to
aromatic amines (1.0 mmol) in dry dichloromethane with
continuous stirring at 0–15 °C for 4–6 h using triethy-
lamine (3.0 mmol) as base [47]. For the synthesis of
benzoic acid prop-2-ynyl esters 2 [7, 8, 11], the benzoyl
chlorides (1.0 mmol) were added to the stirred solution of
propargyl alcohol (1.2 mmol) in dry dichloromethane at
(
C=O str., amide), 1606, 1544, 1448, 1269, 1107,
-
1
033 cm ; HRMS: m/z for C H N O 367.13058
1
19 18 4 4
?
(
[M?H] ).
[1-[2-Oxo-2-(phenylamino)ethyl]-1H-1,2,3-triazol-4-
yl]methyl 4-nitrobenzoate (3c, C18
Light yellow solid; yield: 64 %; m.p.: 206–210 °C; H
NMR (400 MHz, DMSO-d ): d = 5.40 (s, 2H, OCH ),
5.50 (s, 2H, NCH ), 7.09 (t, J = 8.0 Hz, 1H, Ar–H), 7.32
H N O )
15 5 5
1
0
–10 °C for 2–4 h in the presence of N,N-dimethy-
laminopyridine (1.0 mmol). Finally, in the last step, to a
solution of 2-bromo-N-substituted acetamides
6
2
2
1
(d, J = 8.0 Hz, 2H, Ar–H), 7.60 (d, J = 8.0 Hz, 2H, Ar–
H), 8.20 (d, J = 8.0 Hz, 2H, Ar–H), 8.27 (s, 1H, C–H
triazole), 8.35 (d, J = 8.0 Hz, 2H, Ar–H), 10.66 (s, 1H, N–
(
(
1.0 mmol) and benzoic acid prop-2-ynyl esters 2
1.0 mmol) in dimethylformamide:water (8:2) was added
1
3
sodium azide (3.0 mmol) with stirring at 50–60 °C. Then
copper sulfate pentahydrate (0.1 mmol) and sodium ascor-
bate (0.4 mmol) were added to the above reaction mixture
and stirring was continued for 12–18 h. After completion
H amide) ppm;
C NMR (100 MHz, DMSO-d ):
6
d = 52.7, 59.2, 119.7, 124.2, 124.4, 127.3 (C-5 triazole),
129.4, 131.2, 135.2, 138.9, 141.6 (C-4 triazole), 150.8,
164.6 (C=O ester), 165.9 (C=O amide) ppm; FT-IR (KBr):
123

C. P. Kaushik et al.
v = 3251 (N–H str., amide), 3149 (C–H str., triazole ring),
[1-[2-Oxo-2-(p-tolylamino)ethyl]-1H-1,2,3-triazol-4-
yl]methyl 4-nitrobenzoate (3g, C H N O )
3
1
082, 1720 (C=O str., ester), 1699 (C=O str., amide), 1604,
1
9 17 5 5
-
556, 1519, 1442, 1350, 1269, 1099 cm ; HRMS: m/z for
1
1
White solid; yield: 68 %; m.p.: 244–248 °C; H NMR
(400 MHz, DMSO-d ): d = 2.26 (s, 3H, CH ), 5.35 (s, 2H,
OCH ), 5.50 (s, 2H, NCH ), 7.13 (d, J = 8.0 Hz, 2H, Ar–
?
C H N O 382.11374 ([M?H] ).
1
8
15
5
5
6
3
2
2
[
1-[2-Oxo-2-(phenylamino)ethyl]-1H-1,2,3-triazol-4-
H), 7.47 (d, J = 8.0 Hz, 2H, Ar–H), 8.20 (d, J = 8.0 Hz,
yl]methyl 4-fluorobenzoate (3d, C H FN O )
1
8
15
4 3
2
2
H, Ar–H), 8.32 (s, 1H, C–H triazole), 8.35 (d, J = 8.0 Hz,
1
White solid; yield: 72 %; m.p.: 188–192 °C; H NMR
1
H, Ar–H), 10.41 (s, 1H, N–H amide) ppm; C NMR
3
(
400 MHz, DMSO-d ): d = 5.34 (s, 2H, OCH ), 5.44 (s,
6
2
(
100 MHz, DMSO-d ): d = 20.9, 52.7, 59.2, 119.7, 124.2,
6
2
H, NCH ), 7.09 (t, J = 8.0 Hz, 1H, Ar–H), 7.34 (d,
2
1
1
27.3 (C-5 triazole), 129.8, 131.2, 133.2, 135.2, 136.3,
J = 8.0 Hz, 2H, Ar–H), 7.36 (d, J = 8.0 Hz, 2H, Ar–H),
.59 (d, J = 8.0 Hz, 2H, Ar–H), 8.04 (d, J = 8.0 Hz, 2H,
Ar–H), 8.29 (s, 1H, C–H triazole), 10.40 (s, 1H, N–H
41.6 (C-4 triazole), 150.8, 164.5 (C=O ester), 165.9 (C=O
7
amide) ppm; FT-IR (KBr): v = 3251 (N–H str., amide),
3
1
120 (C–H str., triazole ring), 3076, 1718 (C=O str., ester),
-1
1
3
amide) ppm; C NMR (100 MHz, DMSO-d ): d = 52.6,
6
658 (C=O str., amide), 1531, 1354, 1273, 1103 cm
?
;
5
8.5, 116.6, 119.7, 124.2, 126.4, 127.1 (C-5 triazole),
HRMS: m/z for C H N O 396.12949 ([M?H] ).
19 17 5 5
1
29.4, 132.6, 138.9, 142.2 (C-4 triazole), 164.3 (C=O
ester), 165.0, 165.9 (C=O amide) ppm; FT-IR (KBr):
[1-[2-Oxo-2-(p-tolylamino)ethyl]-1H-1,2,3-triazol-4-
v = 3278 (N–H str., amide), 3136 (C–H str., triazole ring),
yl]methyl 4-fluorobenzoate (3h, C H FN O )
1
9
17
4 3
1
3
1
064, 1716 (C=O str., ester), 1678 (C=O str., amide), 1604,
Light green solid; yield: 62 %; m.p.: 206–210 °C; H NMR
(400 MHz, DMSO-d ): d = 2.26 (s, 3H, CH ), 5.34 (s, 2H,
-
548, 1444, 1276, 1151, 1109 cm ; HRMS: m/z for
1
6
3
?
C H FN O 355.11443 ([M?H] ).
1
OCH ), 5.44 (s, 2H, NCH ), 7.13 (d, J = 8.0 Hz, 2H, Ar–
2 2
8
15
4
3
H), 7.36 (d, J = 16.0 Hz, 2H, Ar–H), 7.46 (d, J = 8.0 Hz,
H, Ar–H), 8.04 (d, J = 16.0 Hz, 2H, Ar–H), 8.29 (s, 1H,
13
[
1-[2-Oxo-2-(p-tolylamino)ethyl]-1H-1,2,3-triazol-4-
2
yl]methyl 4-methylbenzoate (3e, C H N O )
2
0
20
4
3
C–H triazole), 10.40 (s, 1H, N–H amide) ppm; C NMR
1
White solid; yield: 68 %; m.p.: 234–238 °C; H NMR
400 MHz, DMSO-d ): d = 2.25 (s, 3H, CH ), 2.38 (s, 3H,
CH ), 5.34 (s, 2H, OCH ), 5.42 (s, 2H, NCH ), 7.13 (d,
(
100 MHz, DMSO-d ): d = 20.9, 52.6, 58.2, 116.3, 119.7,
6
(
6
3
1
1
26.4, 127.1 (C-5 triazole), 129.8, 132.6, 133.2, 136.3,
42.0 (C-4 triazole), 164.3 (C=O ester), 165.0, 165.9 (C=O
3
2
2
J = 8.0 Hz, 2H, Ar–H), 7.34 (d, J = 8.0 Hz, 2H, Ar–H),
.47 (d, J = 8.0 Hz, 2H, Ar–H), 7.87 (d, J = 8.0 Hz, 2H,
Ar–H), 8.28 (s, 1H, C–H triazole), 10.40 (s, 1H, N–H amide)
amide) ppm; FT-IR (KBr): v = 3278 (N–H str., amide),
7
3
1
1
132 (C–H str., triazole ring), 3064, 1716 (C=O str., ester),
678 (C=O str., amide), 1606, 1546, 1278, 1151,
-1
1
3
ppm; C NMR (100 MHz, DMSO-d ): d = 20.9, 21.6,
5
6
103 cm ; HRMS: m/z for C H FN O 369.13495
1
9
17
4 3
2.6, 58.2, 119.7, 127.1 (C-5 triazole), 129.8, 133.2, 136.4,
?
([M?H] ).
1
42.2 (C-4 triazole), 144.3, 164.3 (C=O ester), 165.9 (C=O
amide) ppm; FT-IR (KBr): v = 3253 (N–H str., amide),
[1-[2-(4-Methoxyphenylamino)-2-oxoethyl]-1H-1,2,3-
3
1
140 (C–H str., triazole ring), 3064, 1699 (C=O str., ester),
-
triazol-4-yl]methyl 4-methylbenzoate (3i, C H N O )
2
0 20 4 4
1
1
;
668 (C=O str., amide), 1548, 1438, 1278, 1105 cm
?
White solid; yield: 90 %; m.p.: 218–222 °C; H NMR
(400 MHz, DMSO-d ): d = 2.38 (s, 3H, CH ), 3.72 (s, 3H,
OCH ), 5.32 (s, 2H, OCH ), 5.42 (s, 2H, NCH ), 6.91 (d,
HRMS: m/z for C H N O 365.16000 ([M?H] ).
2
0
20
4
3
6
3
3
2
2
[
1-[2-Oxo-2-(p-tolylamino)ethyl]-1H-1,2,3-triazol-4-
J = 8.0 Hz, 2H, Ar–H), 7.34 (d, J = 8.0 Hz, 2H, Ar–H),
.50 (d, J = 8.0 Hz, 2H, Ar–H), 7.87 (d, J = 8.0 Hz, 2H,
yl]methyl 4-methoxybenzoate (3f, C H N O )
2
0 20 4 4
7
1
White solid; yield: 78 %; m.p.: 230–234 °C; H NMR
400 MHz, DMSO-d ): d = 2.26 (s, 3H, CH ), 3.83 (s, 3H,
OCH ), 5.34 (s, 2H, OCH ), 5.40 (s, 2H, NCH ), 7.05 (d,
Ar–H), 8.27 (s, 1H, C–H triazole), 10.35 (s, 1H, N–H
13
(
6
3
amide) ppm; C NMR (100 MHz, DMSO-d ): d = 21.6,
6
3
2
2
52.6, 55.6, 58.2, 114.5, 121.2, 127.1 (C-5 triazole), 129.8,
J = 8.0 Hz, 2H, Ar–H), 7.13 (d, J = 8.0 Hz, 2H, Ar–H),
.47 (d, J = 8.0 Hz, 2H, Ar–H), 7.93 (d, J = 8.0 Hz, 2H,
Ar–H), 8.26 (s, 1H, C–H triazole), 10.40 (s, 1H, N–H
132.0, 142.2 (C-4 triazole), 144.3, 156.0, 164.3 (C=O
7
ester), 165.9 (C=O amide) ppm; FT-IR (KBr): v = 3248
N–H str., amide), 3138 (C–H str., triazole ring), 3064,
(
1
3
amide) ppm; C NMR (100 MHz, DMSO-d ): d = 20.9,
6
1
1
3
699 (C=O str., ester), 1664 (C=O str., amide), 1610, 1550,
-
5
1
1
2.6, 56.0, 58.1, 114.6, 119.7, 122, 127.0 (C-5 triazole),
29.8, 131.8, 133.2, 136.4, 142.3 (C-4 triazole), 163.8,
64.3 (C=O ester), 165.6 (C=O amide) ppm; FT-IR (KBr):
1
450, 1267, 1103 cm ; HRMS: m/z for C H N O
0 20 4 4
2
?
81.15867 ([M?H] ).
v = 3251 (N–H str., amide), 3140 (C–H str., triazole ring),
[1-[2-(4-Methoxyphenylamino)-2-oxoethyl]-1H-1,2,3-
triazol-4-yl]methyl 4-methoxybenzoate (3j, C H N O )
3
1
3
066, 1693 (C=O str., ester), 1668 (C=O str., amide), 1606,
-
2
0 20 4 5
1
1
546, 1273, 1103 cm ; HRMS: m/z for C H N O
0 20 4 4
White solid; yield: 78 %; m.p.: 188–192 °C; H NMR
(400 MHz, DMSO-d ): d = 3.72 (s, 3H, OCH ), 3.83 (s,
2
?
81.15515 ([M?H] ).
6
3
1
23

Synthesis, antimicrobial activity, and QSAR studies of amide-ester linked 1,4-disubstituted…
3
H, OCH ), 5.32 (s, 2H, OCH ), 5.40 (s, 2H, NCH ), 6.91
3
H), 7.33 (d, J = 8.0 Hz, 2H, Ar–H), 7.60 (d, J = 8.0 Hz,
2H, Ar–H), 7.87 (d, J = 8.0 Hz, 2H, Ar–H), 8.29 (s, 1H,
2
2
(
d, J = 8.0 Hz, 2H, Ar–H), 7.05 (d, J = 8.0 Hz, 2H, Ar–
H), 7.50 (d, J = 8.0 Hz, 2H, Ar–H), 7.93 (d, J = 8.0 Hz,
H, Ar–H), 8.27 (s, 1H, C–H triazole), 10.35 (s, 1H, N–H
1
C–H triazole), 10.56 (s, 1H, N–H amide) ppm; C NMR
3
2
(100 MHz, DMSO-d ): d = 21.6, 52.6, 58.2, 115.9, 116.1,
6
1
3
amide) ppm; C NMR (100 MHz, DMSO-d ): d = 52.6,
5
121.5, 127.1 (C-5 triazole), 129.8, 135.2, 142.2 (C-4
triazole), 144.3, 157.5, 159.9, 164.6 (C=O ester), 165.9
(C=O amide) ppm; FT-IR (KBr): v = 3253 (N–H str.,
amide), 3151 (C–H str., triazole ring), 3070, 1703 (C=O
str., ester), 1672 (C=O str., amide), 1604, 1558, 1510,
6
5.6, 56.0, 58.1, 114.6, 121.2, 122.0, 127.0 (C-5 triazole),
1
31.8, 132.0, 142.3 (C-4 triazole), 156.0, 163.8, 164.1
(
C=O ester), 165.6 (C=O amide) ppm; FT-IR (KBr):
v = 3277 (N–H str., amide), 3136 (C–H str., triazole ring),
-
1
3
1
3
060, 1691 (C=O str., ester), 1676 (C=O str., amide), 1606,
-
1274, 1158, 1101 cm ; HRMS: m/z for C H FN O
19 17 4 3
1
?
367.12173 ([M?H] ).
548, 1263, 1107 cm ; HRMS: m/z for C H N O
0 20 4 5
2
?
97.14987 ([M?H] ).
[
1-[2-(4-Fluorophenylamino)-2-oxoethyl]-1H-1,2,3-
[
1-[2-(4-Methoxyphenylamino)-2-oxoethyl]-1H-1,2,3-
triazol-4-yl]methyl 4-methoxybenzoate
triazol-4-yl]methyl 4-nitrobenzoate (3k, C H N O )
1
9
17
5
1
6
(3n, C H FN O )
17
1
9
4 4
1
White solid; yield: 65 %; m.p.: 196–200 °C; H NMR
Light green solid; yield: 78 %; m.p.: 212–216 °C; H NMR
(400 MHz, DMSO-d ): d = 3.83 (s, 3H, OCH ), 5.34 (s,
(
400 MHz, DMSO-d ): d = 3.72 (s, 3H, OCH ), 5.32 (s,
6
3
6
3
2
H, OCH ), 5.50 (s, 2H, NCH ), 6.91 (d, J = 8.0 Hz, 2H,
2 2
2H, OCH ), 5.41 (s, 2H, NCH ), 7.05 (d, J = 8.0 Hz, 2H,
2 2
Ar–H), 7.50 (d, J = 8.0 Hz, 2H, Ar–H), 8.20 (d,
J = 8.0 Hz, 2H, Ar–H), 8.32 (s, 1H, C–H triazole), 8.35
Ar–H), 7.18 (d, J = 8.0 Hz, 2H, Ar–H), 7.60 (d,
J = 8.0 Hz, 2H, Ar–H), 7.93 (d, J = 8.0 Hz, 2H, Ar–H),
(
d, J = 8.0 Hz, 2H, Ar–H), 10.35 (s, 1H, N–H amide)
1
8
.27 (s, 1H, C–H triazole), 10.55 (s, 1H, N–H amide) ppm;
3
1
3
ppm; C NMR (100 MHz, DMSO-d ): d = 52.6, 55.6,
5
6
C NMR (100 MHz, DMSO-d ): d = 52.6, 56.0, 58.1,
6
9.2, 114.5, 121.2, 124.4, 127.3 (C-5 triazole), 131.2,
1
1
14.6, 115.9, 121.5, 122.0, 127.0 (C-5 triazole), 131.8,
1
32.0, 135.2, 141.6 (C-4 triazole), 150.8, 156.0, 164.5
35.2, 142.3 (C-4 triazole), 159.9, 163.8, 164.3 (C=O
(
C=O ester), 165.6 (C=O amide) ppm; FT-IR (KBr):
ester), 165.8 (C=O amide) ppm; FT-IR (KBr): v = 3248
N–H str., amide), 3155 (C–H str., triazole ring), 3072,
v = 3230 (N–H str., amide), 3120 (C–H str., triazole ring),
(
3
1
066, 1716 (C=O str., ester), 1656 (C=O str., amide), 1602,
1
1
703 (C=O str., ester), 1683 (C=O str., amide), 1608, 1556,
-
-
527, 1456, 1352, 1269, 1103 cm ; HRMS: m/z for
1
1
269, 1101 cm
;
HRMS: m/z for C H FN O
19 17 4 4
?
?
C H N O 412.12063 ([M?H] ).
6
1
9
17
5
385.12134 ([M?H] ).
[
1-[2-(4-Methoxyphenylamino)-2-oxoethyl]-1H-1,2,3-
[
1-[2-(4-Fluorophenylamino)-2-oxoethyl]-1H-1,2,3-
triazol-4-yl]methyl 4-fluorobenzoate (3l, C H FN O )
1
9
17
4 4
triazol-4-yl]methyl 4-nitrobenzoate (3o, C H FN O )
1
8
14
5 5
1
1
White solid; yield: 80 %; m.p.: 208–212 °C; H NMR
White solid; yield: 77 %; m.p.: 214–218 °C; H NMR
(400 MHz, DMSO-d ): d = 5.38 (s, 2H, OCH ), 5.50 (s,
2H, NCH ), 7.17 (d, J = 8.0 Hz, 2H, Ar–H), 7.61 (d,
(
400 MHz, DMSO-d ): d = 3.72 (s, 3H, OCH ), 5.32 (s,
6
3
6
2
2
H, OCH ), 5.44 (s, 2H, NCH ), 6.91 (d, J = 8.0 Hz, 2H,
2 2
2
Ar–H), 7.36 (d, J = 16.0 Hz, 2H, Ar–H), 7.49 (d,
J = 8.0 Hz, 2H, Ar–H), 8.04 (d, J = 16.0 Hz, 2H, Ar–
H), 8.29 (s, 1H, C–H triazole), 10.35 (s, 1H, N–H amide)
J = 8.0 Hz, 2H, Ar–H), 8.20 (d, J = 8.0 Hz, 2H, Ar–H),
8
1
.33 (s, 1H, C–H triazole), 8.35 (d, J = 8.0 Hz, 2H, Ar–H),
1
0.64 (s, 1H, N–H amide) ppm; C NMR (100 MHz,
3
1
3
ppm; C NMR (100 MHz, DMSO-d ): d = 52.6, 55.6,
6
DMSO-d ): d = 52.6, 59.2, 115.9, 121.4, 124.4, 127.3 (C-5
6
5
8.5, 114.5, 116.3, 121.2, 126.5, 127.1 (C-5 triazole),
triazole), 131.2, 135.2, 141.7 (C-4 triazole), 150.8, 157.5,
1
32.0, 132.6, 142.0 (C-4 triazole), 156.0, 164.4 (C=O
159.9, 164.5 (C=O ester), 165.9 (C=O amide) ppm; FT-IR
ester), 165.0, 165.9 (C=O amide) ppm; FT-IR (KBr):
(KBr): v = 3217 (N–H str., amide), 3153 (C–H str.,
v = 3277 (N–H str., amide), 3136 (C–H str., triazole ring),
triazole ring), 3066, 1714 (C=O str., ester), 1668 (C=O
-
1
;
1
1
3
716 (C=O str., ester), 1678 (C=O str., amide), 1604, 1548,
str., amide), 1618, 1560, 1516, 1352, 1271, 1105 cm
?
HRMS: m/z for C H FN O 400.10425 ([M?H] ).
-
280, 1148, 1111 cm ; HRMS: m/z for C H FN O
1
1
9
17
4
4
1
8
14
5 5
?
83.11694 ([M?H] ).
[
1-[2-(4-Fluorophenylamino)-2-oxoethyl]-1H-1,2,3-
[
1-[2-(4-Fluorophenylamino)-2-oxoethyl]-1H-1,2,3-
triazol-4-yl]methyl 4-methylbenzoate
3m, C H FN O )
triazol-4-yl]methyl 4-fluorobenzoate
(3p, C H F N O )
1
8 14 2 4 3
1
(
Light greenish solid; yield: 68 %; m.p.: 206–210 °C; H
NMR (400 MHz, DMSO-d ): d = 5.34 (s, 2H, OCH ),
5.44 (s, 2H, NCH ), 7.18 (d, J = 8.0 Hz, 2H, Ar–H), 7.36
1
9
17
4 3
1
White solid; yield: 76 %; m.p.: 230–234 °C; H NMR
400 MHz, DMSO-d ): d = 2.38 (s, 3H, CH ), 5.36 (s, 2H,
OCH ), 5.42 (s, 2H, NCH ), 7.18 (d, J = 8.0 Hz, 2H, Ar–
6
2
(
6
3
2
(d, J = 8.0 Hz, 2H, Ar–H), 7.61 (d, J = 8.0 Hz, 2H, Ar–
2
2
123

C. P. Kaushik et al.
H), 8.04 (d, J = 8.0 Hz, 2H, Ar–H), 8.29 (s, 1H, C–H
triazole), 150.8, 164.5 (C=O ester), 165.6 (C=O amide)
ppm; FT-IR (KBr): v = 3246 (N–H str., amide), 3170 (C–
H str., triazole ring), 3047, 1714 (C=O str., ester), 1686
1
triazole), 10.40 (s, 1H, N–H amide) ppm; C NMR
3
(
100 MHz, DMSO-d ): d = 52.6, 58.5, 115.9, 121.5,
6
-
1
1
26.4, 127.1 (C-5 triazole), 132.7, 135.2, 142.2 (C-4
(C=O str., amide), 1600, 1533, 1278, 1112 cm ; HRMS:
?
m/z for C H BrN O 458.03157 ([M?H] ).
triazole), 159.9, 164.3 (C=O ester), 165.0, 165.9 (C=O
1
8
14
5 5
amide) ppm; FT-IR (KBr): v = 3280 (N–H str., amide),
[
1-[2-(4-Bromophenylamino)-2-oxoethyl]-1H-1,2,3-
triazol-4-yl]methyl 4-fluorobenzoate
3t, C H BrFN O )
3
1
140 (C–H str., triazole ring), 3055, 1714 (C=O str., ester),
-
1
;
676 (C=O str., amide), 1606, 1550, 1278, 1101 cm
?
(
18 14
4 3
HRMS: m/z for C H F N O 373.10470 ([M?H] ).
3
1
8
14
2
4
1
Light green solid; yield: 79 %; m.p.: 224–228 °C; H NMR
(400 MHz, DMSO-d ): d = 5.37 (s, 2H, OCH ), 5.44 (s, 2H,
NCH ), 7.36 (d, J = 8.0 Hz, 2H, Ar–H), 7.52 (d, J = 8.0 Hz,
[
1-[2-(4-Bromophenylamino)-2-oxoethyl]-1H-1,2,3-
triazol-4-yl]methyl 4-methylbenzoate
3q, C H BrN O )
6
2
2
(
2H, Ar–H), 7.56 (d, J = 8.0 Hz, 2H, Ar–H), 8.04 (d,
J = 8.0 Hz, 2H, Ar–H), 8.29 (s, 1H, C–H triazole), 10.66 (s,
1
9
17
4 3
1
White solid; yield: 72 %; m.p.: 230–234 °C; H NMR
400 MHz, DMSO-d ): d = 2.38 (s, 3H, CH ), 5.36 (s, 2H,
OCH ), 5.42 (s, 2H, NCH ), 7.33 (d, J = 8.0 Hz, 2H, Ar–
13
(
1H, N–H amide) ppm; C NMR (100 MHz, DMSO-d6):
d = 52.7, 58.5, 115.9, 116.6, 121.6, 126.5, 127.1 (C-5 triazole),
132.2, 132.7, 138.2, 142.1 (C-4 triazole), 164.8 (C=O ester),
165.0 (C=O amide) ppm; FT-IR (KBr): v = 3275 (N–H str.,
amide), 3128 (C–H str., triazole ring), 1714 (C=O str., ester),
6
3
2
2
H), 7.52 (d, J = 8.0 Hz, 2H, Ar–H), 7.56 (d, J = 8.0 Hz,
2
H, Ar–H), 7.87 (d, J = 8.0 Hz, 2H, Ar–H), 8.29 (s, 1H,
1
C–H triazole), 10.64 (s, 1H, N–H amide) ppm; C NMR
3
-1
(
(
100 MHz, DMSO-d ): d = 21.6, 52.6, 58.1, 121.6, 127.1
C-5 triazole), 129.8, 132.2, 138.2, 142.2 (C-4 triazole),
1680 (C=O str., amide), 1602, 1543, 1278, 1103 cm ; HRMS:
?
m/z for C H BrFN O 433.03168 ([M?H] ).
6
18
14
4 3
1
44.3, 164.6 (C=O ester), 165.6 (C=O amide) ppm; FT-IR
KBr): v = 3246 (N–H str., amide), 3143 (C–H str.,
triazole ring), 3051, 1703 (C=O str., ester), 1674 (C=O
[
1-[2-(4-Nitrophenylamino)-2-oxoethyl]-1H-1,2,3-
(
triazol-4-yl]methyl 4-methylbenzoate (3u, C H N O )
1
9 17 5 5
1
Yellow solid; yield: 96 %; m.p.: 226–230 °C; H NMR
400 MHz, DMSO-d ): d = 2.37 (s, 3H, CH ), 5.43 (s, 2H,
OCH ), 5.47 (s, 2H, NCH ), 7.33 (d, J = 8.0 Hz, 2H, Ar–
-
1
str., amide), 1606, 1546, 1274, 1103 cm ; HRMS: m/z for
?
C H BrN O 429.06156 ([M?H] ).
(
6
3
1
9
17
4 3
2
2
[
1-[2-(4-Bromophenylamino)-2-oxoethyl]-1H-1,2,3-
H), 7.84 (d, J = 8.0 Hz, 2H, Ar–H), 7.86 (d, J = 12.0 Hz,
2H, Ar–H), 8.24 (d, J = 12.0 Hz, 2H, Ar–H), 8.31 (s, 1H,
13
triazol-4-yl]methyl 4-methoxybenzoate (3r, C H BrN O )
4 4
19
17
1
White solid; yield: 70 %; m.p.: 226–230 °C; H NMR
C–H triazole), 11.10 (s, 1H, N–H amide) ppm; C NMR
(
400 MHz, DMSO-d ): d = 3.83 (s, 3H, OCH ), 5.36 (s,
(100 MHz, DMSO-d ): d = 21.6, 52.8, 58.2, 119.5, 125.6,
6
3
6
2
H, OCH ), 5.40 (s, 2H, NCH ), 7.05 (d, J = 8.0 Hz, 2H,
2
127.1 (C-5 triazole), 129.7, 129.8, 142.3 (C-4 triazole),
143.1, 144.3, 145.0, 164.5 (C=O ester), 165.9 (C=O amide)
ppm; FT-IR (KBr): v = 3219 (N–H str., amide), 3153 (C–
H str., triazole ring), 3078, 1710 (C=O str., ester), 1683
2
Ar–H), 7.51–7.57 (m, 4H, Ar–H), 7.93 (d, J = 8.0 Hz, 2H,
Ar–H), 8.27 (s, 1H, C–H triazole), 10.64 (s, 1H, N–H
1
amide) ppm; C NMR (100 MHz, DMSO-d ): d = 52.7,
3
6
-
1
5
6.0, 58.1, 114.6, 121.6, 122.0, 127.0 (C-5 triazole), 131.8,
(C=O str., amide), 1556, 1512, 1348, 1271, 1103 cm
?
HRMS: m/z for C H N O 396.13101 ([M?H] ).
;
1
32.2, 138.2, 142.3 (C-4 triazole), 163.8, 164.9 (C=O
1
9 17 5 5
ester), 165.6 (C=O amide) ppm; FT-IR (KBr): v = 3277
N–H str., amide), 3136 (C–H str., triazole ring), 3066,
[
1-[2-(4-Nitrophenylamino)-2-oxoethyl]-1H-1,2,3-
triazol-4-yl]methyl 4-methoxybenzoate
3v, C H N O )
(
1
1
4
708 (C=O str., ester), 1681 (C=O str., amide), 1604, 1539,
(
-
485, 1267, 1105 cm ; HRMS: m/z for C H BrN O
1
19 17 5 6
1
9
17
4
4
1
Light yellow solid; yield: 98 %; m.p.: 234–238 °C; H
NMR (400 MHz, DMSO-d ): d = 3.83 (s, 3H, OCH ),
?
45.05141 ([M?H] ).
6
3
[
1-[2-(4-Bromophenylamino)-2-oxoethyl]-1H-1,2,3-
5.37 (s, 2H, OCH ), 5.41 (s, 2H, NCH ), 7.05 (d,
2 2
triazol-4-yl]methyl 4-nitrobenzoate (3s, C H BrN O )
5 5
J = 8.0 Hz, 2H, Ar–H), 7.86 (d, J = 8.0 Hz, 2H, Ar–H),
7.93 (d, J = 8.0 Hz, 2H, Ar–H), 8.25 (d, J = 8.0 Hz, 2H,
Ar–H), 8.28 (s, 1H, C–H triazole), 11.11 (s, 1H N–H,
1
8
14
1
Light yellowish solid; yield: 76 %; m.p.: 228–232 °C; H
NMR (400 MHz, DMSO-d ): d = 5.38 (s, 2H, OCH ),
6
2
1
3
5
.50 (s, 2H, NCH ), 7.52 (d, J = 8.0 Hz, 2H, Ar–H), 7.56
2
amide) ppm; C NMR (100 MHz, DMSO-d ): d = 52.8,
6
(
d, J = 8.0 Hz, 2H, Ar–H), 8.20 (d, J = 8.0 Hz, 2H, Ar–
56.0, 58.1, 114.6, 119.5, 122.0, 126.5, 127.1 (C-5 triazole),
131.8, 142.3 (C-4 triazole), 143.1, 145.0, 163.8, 164.9
(C=O ester), 165.9 (C=O amide) ppm; FT-IR (KBr):
v = 3253 (N–H str., amide), 3155 (C–H str., triazole ring),
3082, 1708 (C=O str., ester), 1681 (C=O str., amide), 1604,
H), 8.35 (d, J = 8.0 Hz, 2H, Ar–H), 8.33 (s, 1H, C–H
1
triazole), 10.64 (s, 1H, N–H amide) ppm; C NMR
3
(
(
100 MHz, DMSO-d ): d = 52.7, 59.7, 121.6, 124.4, 127.3
C-5 triazole), 131.2, 132.2, 135.2, 138.2, 141.7 (C-4
6
1
23

Synthesis, antimicrobial activity, and QSAR studies of amide-ester linked 1,4-disubstituted…
-
556, 1506, 1348, 1265, 1103 cm ; HRMS: m/z for
1
-1
;
1
(C=O str., amide), 1608, 1548, 1454, 1267, 1101 cm
?
HRMS: m/z for C H N O 401.15076 ([M?H] ).
?
C H N O 412.12053 ([M?H] ).
1
9
17
5
6
23 20 4 3
[
1-[2-(4-Nitrophenylamino)-2-oxoethyl]-1H-1,2,3-
[1-[2-(Naphthalen-1-ylamino)-2-oxoethyl]-1H-1,2,3-
triazol-4-yl]methyl 4-methoxybenzoate (3z, C H N O )
triazol-4-yl]methyl-4-nitrobenzoate (3w, C H N O )
7
1
8
14
6
23 20 4 4
1
1
Light yellow solid; yield: 80 %; m.p.: 224–228 °C; H
NMR (400 MHz, DMSO-d ): d = 5.48 (s, 2H, OCH ),
White solid; yield: 73 %; m.p.: 216–220 °C; H NMR
(400 MHz, DMSO-d ): d = 3.83 (s, 3H, OCH ), 5.41 (s,
6
2
6
3
5
.51 (s, 2H, NCH ), 7.83 (d, J = 8.0 Hz, 2H, Ar–H), 8.19
2
2H, OCH ), 5.58 (s, 2H, NCH ), 7.05 (d, J = 8.0 Hz, Ar–
2 2
(
d, J = 8.0 Hz, 2H, Ar–H), 8.24 (d, J = 8.0 Hz, 2H, Ar–
H, 2H), 7.52 (d, J = 8.0 Hz, 1H, Ar–H), 7.58 (d,
J = 8.0 Hz, 1H, Ar–H), 7.59 (d, J = 8.0 Hz, 1H, Ar–H),
7.72 (d, J = 8.0 Hz, 1H, Ar–H), 7.80 (d, J = 8.0 Hz, 1H,
Ar–H), 7.92–7.97 (m, 3H, Ar–H), 8.18 (d, J = 8.0 Hz, 1H,
Ar–H), 8.33 (s, 1H, C–H triazole), 10.49 (s, 1H, N–H
H), 8.29 (s, 1H, C–H triazole), 8.35 (d, J = 8.0 Hz, 2H,
3
Ar–H), 11.12 (s, 1H, N–H amide) ppm; C NMR
1
(
100 MHz, DMSO-d ): d = 52.8, 59.2, 119.5, 124.4,
6
1
25.6, 127.3 (C-5 triazole), 131.2, 135.2, 141.8 (C-4
triazole), 143.1, 145.0, 150.8, 164.5 (C=O ester), 165.8
C=O amide) ppm; FT-IR (KBr): v = 3222 (N–H str.,
1
3
amide) ppm; C NMR (100 MHz, DMSO-d ): d = 52.6,
6
(
56.0, 58.1, 114.6, 122.0, 123.1, 126.0, 126.2, 126.5, 126.7,
127.1 (C-5 triazole), 128.0, 128.7, 131.8, 133.2, 134.2,
142.3 (C-4 triazole), 163.8, 164.3 (C=O ester), 165.6 (C=O
amide) ppm; FT-IR (KBr): v = 3236 (N–H str., amide),
3161 (C–H str., triazole ring), 3049, 1705 (C=O str., ester),
amide), 3155 (C–H str., triazole ring), 3049, 1722 (C=O
str., ester), 1685 (C=O str., amide), 1587, 1516, 1342,
-
1
1
269, 1103 cm ; HRMS: m/z for C H N O 425.08582
18 14 6 7
?
[M?H] ).
(
1
680 (C=O str., amide), 1600, 1550, 1454, 1269,
-
1
[
1-[2-(4-Nitrophenylamino)-2-oxoethyl]-1H-1,2,3-
1112 cm ; HRMS: m/z for C H N O 417.15579
23 20 4 4
?
triazol-4-yl]methyl 4-fluorobenzoate (3x, C H FN O )
8
([M?H] ).
1-[2-(Naphthalen-1-ylamino)-2-oxoethyl]-1H-1,2,3-
triazol-4-yl]methyl 4-nitrobenzoate (3z , C H N O )
1
14
5 5
1
White solid; yield: 60 %; m.p.: 230–234 °C; H NMR
[
(
400 MHz, DMSO-d ): d = 5.44 (s, 2H, OCH ), 5.49 (s,
6
2
1
22 17 5 5
2
H, NCH ), 7.36 (d, J = 8.8 Hz, 2H, Ar–H), 7.87 (d,
2
1
White solid; yield: 78 %; m.p.: 204–208 °C; H NMR
J = 8.8 Hz, 2H, Ar–H), 8.03 (d, J = 8.8 Hz, 2H, Ar–H),
(
400 MHz, DMSO-d ): d = 5.52 (s, 2H, OCH ), 5.59 (s,
6
2
8
1
.24 (d, J = 8.8 Hz, 2H, Ar–H), 8.32 (s, 1H, C–H triazole),
1
1.11 (s, 1H, N–H amide) ppm; C NMR (100 MHz,
3
2H, NCH ), 7.51 (d, J = 8.0 Hz, 1H, Ar–H), 7.57 (d,
2
J = 8.0 Hz, 1H, Ar–H), 7.59 (d, J = 8.0 Hz, 1H, Ar–H),
.72(d, J = 8.0 Hz, 1H, Ar–H), 7.80(d, J = 8.0 Hz, 1H, Ar–
DMSO-d ): d = 52.8, 58.5, 116.5, 119.5, 125.5, 126.4,
6
7
1
27.1 (C-5 triazole), 132.7, 142.1 (C-4 triazole), 143.0,
H), 7.96 (d, J = 8.0 Hz, 1H, Ar–H), 8.17 (d, J = 8.0 Hz, 1H,
Ar–H), 8.20 (d, J = 8.0 Hz, 2H, Ar–H), 8.34 (s, 1H, C–H
triazole), 8.37 (d, J = 8.0 Hz, 2H, Ar–H), 10.47 (s, 1H, N–H
1
45.1, 164.4 (C=O ester), 165.0, 165.8 (C=O amide) ppm;
FT-IR (KBr): v = 3217 (N–H str., amide), 3159 (C–H str.,
triazole ring), 3051, 1708 (C=O str., ester), 1687 (C=O str.,
1
3
-
amide), 1602, 1573, 1508, 1344, 1278, 1112 cm ; HRMS:
1
amide) ppm; C NMR (100 MHz, DMSO-d
): d = 52.6,
6
?
m/z for C H FN O 398.09097 ([M?H] ).
59.2, 122.0, 123.1, 124.4, 126.0, 126.2, 126.5, 126.7, 127.4
1
8
14
5 5
(
(
C-5 triazole), 128.0, 128.7, 131.2, 133.2, 134.2, 135.2, 141.7
C-4 triazole), 150.8, 164.5 (C=O ester), 165.6 (C=O amide)
[
1-[2-(Naphthalen-1-ylamino)-2-oxoethyl]-1H-1,2,3-
ppm; FT-IR (KBr): v = 3304 (N–H str., amide), 3155 (C–H
triazol-4-yl]methyl 4-methylbenzoate (3y, C H N O )
2
3 20 4 3
1
str., triazole ring), 3089, 1714 (C=O str., ester), 1670 (C=O
White solid; yield: 78 %; m.p.: 236–240 °C; H NMR
400 MHz, DMSO-d ): d = 2.38 (s, 3H, CH ), 5.47 (s, 2H,
OCH ), 5.58 (s, 2H, NCH ), 7.33 (d, J = 8.0 Hz, 2H, Ar–
-1
str., amide), 1600, 1554, 1525, 1352, 1274, 1112 cm ;
?
HRMS: m/z for C H N O 432.13090 ([M?H] ).
(
6
3
2
2 17 5 5
2
2
H), 7.52 (d, J = 8.0 Hz, 1H, Ar–H), 7.57 (d, J = 8.0 Hz,
H, Ar–H), 7.59 (d, J = 8.0 Hz, 1H, Ar–H), 7.72 (d,
J = 8.0 Hz, 1H, Ar–H), 7.80 (d, J = 8.0 Hz, 1H, Ar–H),
.87 (d, J = 8.0 Hz, 2H, Ar–H), 7.96 (d, J = 8.0 Hz, 1H,
Ar–H), 8.18 (d, J = 8.0 Hz, 1H, Ar–H), 8.36 (s, 1H, C–H
[1-[2-(Naphthalen-1-ylamino)-2-oxoethyl]-1H-1,2,3-
triazol-4-yl]methyl 4-fluorobenzoate
(3z , C H FN O )
1
2
22 17
4 3
1
7
Light green solid; yield: 87 %; m.p.: 220–224 °C; H NMR
(400 MHz, DMSO-d ): d = 5.45 (s, 2H, OCH ), 5.59 (s,
2H, NCH ), 7.36 (d, J = 8.0 Hz, 2H, Ar–H), 7.50 (s, 1H,
6
2
1
3
triazole), 10.48 (s, 1H, N–H amide) ppm; C NMR
2
(
100 MHz, DMSO-d ): d = 21.6, 52.6, 58.2, 122.0, 123.1,
26.0, 126.2, 126.5, 126.7, 127.1 (C-5 triazole), 127.2,
28.0, 128.7, 129.4, 129.8, 133.2, 134.2, 142.2 (C-4
Ar–H), 7.58–7.59 (m, 2H, Ar–H), 7.72 (d, J = 8.0 Hz, 1H,
Ar–H), 7.80 (d, J = 8.0 Hz, 1H, Ar–H), 7.96 (d,
J = 8.0 Hz, 1H, Ar–H), 8.04 (d, J = 8.0 Hz, 2H, Ar–H),
8.18 (s, 1H, Ar–H), 8.36 (s, 1H, C–H triazole), 10.54 (s,
6
1
1
triazole), 144.3, 164.3 (C=O ester), 165.6 (C=O amide)
ppm; FT-IR (KBr): v = 3253 (N–H str., amide), 3151 (C–
H str., triazole ring), 3047, 1703 (C=O str., ester), 1666
1
3
1H, N–H amide) ppm; C NMR (100 MHz, DMSO-d6):
d = 52.6, 58.6, 116.6, 122.0, 123.1, 126.0, 126.2, 126.5,
123

C. P. Kaushik et al.
1
1
26.6, 127.2 (C-5 triazole), 128.0, 128.7, 132.7, 133.2,
34.2, 142.1 (C-4 triazole), 164.4 (C=O ester), 165.0, 165.6
given in terms of minimum inhibitory concentration (MIC)
as furnished in Table 1.
(
C=O amide), 166.9 ppm; FT-IR (KBr): v = 3253 (N–H
str., amide), 3146 (C–H str., triazole ring), 3032, 1707
QSAR studies
(
C=O str., ester), 1664 (C=O str., amide), 1600, 1550,
1
-
1
4
436, 1273, 1101 cm ; HRMS: m/z for C H FN O
22 17 4 3
?
05.13562 ([M?H] ).
The structures of amide-ester linked 1,4-disubstituted
1,2,3-triazoles 3a–3z were first pre-optimized with the
2
?
molecular mechanics force field (MM ) procedure
included in Hyperchem 6.03 [50] and the resulting
geometries are further refined by means of the semiem-
pirical method parametric method-3 (PM3). We chose a
Antibacterial activity
All the synthesized 1,4-disubstituted 1,2,3-triazoles 3a–3z2
were screened for in vitro antibacterial activity against two
Gram positive bacteria, S. aureus (MTCC 1430) and B.
subtilis (MTCC 2423) and one Gram negative bacteria,
E. coli (MTCC 739). Dilutions of test and standard com-
pounds were prepared in double strength nutrient broth
´
˚
gradient norm limit of 0.01 kcal/A for the geometry
optimization. The lowest energy structure was used for
each molecule to calculate physicochemical properties
using TSAR 3.3 software for Windows [51]. Further, the
regression analysis was performed using the SPSS soft-
ware package [52].
[
48], while dimethylsulfoxide was used as solvent control.
The in vitro activities of synthesized triazoles were tested
3
in 1.0 cm nutrient broth (1000 mm ) taken in each test
3
Acknowledgments Authors wish acknowledge University Grants
Commission, New Delhi for financial assistance to support research
work through Major Research Project sanctioned to Dr. C. P. Kaushik
tube by standard serial dilution method [49]. To the first
3
test tube, 1.0 cm of drug solution (100 lg/cm ) was added
aseptically to get the concentration of 50 lg/cm . From this
dilution, other concentrations were prepared aseptically by
3
3
(
CPK).
serial dilution technique to get final concentration 25, 12.5,
3
6
.25, 3.12, 1.56, and 0.78 lg/cm . All the test tubes were
aseptically inoculated by desired bacterial suspension of
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