Synthesis of new triazole tethered derivatives of curcumin and their antibacterial and antifungal properties

Article abstract of DOI:10.1007/s13738-018-1524-7

New derivatives of curcumin connected to 1,2,3-triazole ring were synthesized by Knoevenagel reaction of the middle carbon with aromatic aldehydes, followed by alkyne-azide 1,3-dipolar cycloaddition. These new compounds were evaluated for their antimicrob

Full text of DOI:10.1007/s13738-018-1524-7

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-018-1524-7
ORIGINAL PAPER
Synthesis of new triazole tethered derivatives of curcumin and their
antibacterial and antifungal properties
Maryam Esmaeelzadeh1 · Peyman Salehi1 · Morteza Bararjanian1 · Sajjad Gharaghani2
Received: 14 September 2018 / Accepted: 9 October 2018
© Iranian Chemical Society 2018
Abstract
New derivatives of curcumin connected to 1,2,3-triazole ring were synthesized by Knoevenagel reaction of the middle carbon
with aromatic aldehydes, followed by alkyne-azide 1,3-dipolar cycloaddition. These new compounds were evaluated for their
antimicrobial activity against Staphylococcus aureus, Escherichia coli, Bacillus cereus and Pseudomonas aeruginosa. Many
of the synthesized compounds showed a better antibacterial and antifungal activity in comparison with the parent molecule,
curcumin. Then quantitative structure–activity relationship (QSAR) modeling was performed to determine the structural
descriptors which correlate to the antibacterial and antifungal activities with the synthesized curcumin derivatives. QSAR
study showed a good agreement between the experimental results and the predicted values.
Keywords Antimicrobial activities · Click chemistry · Curcumin · Natural lead compound · Knoevenagel · QSAR
Introduction
disease, cardiovascular disorders, psoriasis and almost all
types of cancer [9]. Isolation of curcumin from turmeric was
reported in 1815 for the first time [10] and a century after its
isolation, Lamp and Milobedzka reported synthesis of cur-
cumin in 1913 [11]. There are four positions of this diaryl-
heptanoid for structural modifications: (a) active methylene
group, (b) double bonds, (c) diketo group, and (d) hydroxyl
groups of aryl side chains (Fig. 1) [12].
Natural products derived from plants have been used for
different purposes by human in history. Many of these prod-
ucts are secondary metabolites with defensive role to plants
against infections and diseases [1]. Natural products are
rich sources of lead and hit compounds [2]. More than half
of the drugs are natural compounds or their semisynthetic
derivatives [3]. Among different natural products, curcumin
1 is a good candidate for drug discovery and development
of medicine [4]. Curcumin is a phytochemical with a low
molecular weight [5] that is the major active constituent of
Curcuma Longa [6]. This diarylheptanoid is being used daily
by millions of people in many countries as a spice because
of its flavor and yellow color. Curcumin is a dietary natural
product [7] that has been used in traditional medicine for
treatment of jaundice, rheumatoid arthritis, urinary tract dis-
eases, indigestion and insect bites [8]. In addition, curcumin
has been used to treat various disorders such as Crohn’s
Knoevenagel condensation between an active methylene
group and an appropriate aldehyde is an important reaction
for C=C bond formation [13]. Methylene group of curcumin
is a proper choice for Knoevenagel condensation. Reaction
between curcumin and an aldehyde has been catalyzed by
several bases such as pyridine [14], piperidine [4, 15, 16]
and triphenylphosphine [17].
Curcumin has a broad-spectrum of antimicrobial activ-
ities such as antibacterial and antiviral properties [18].
Since the consumption of curcumin is safe even at high
doses (12 g/day), this compound is a good candidate for
boosting its properties through the semisynthetic pathways
[18]. Curcumin has shown strong antibacterial potency
against some Gram-positive and Gram-negative bacteria
by damaging their membranes [19]. Mono and di-glu-
coside derivatives of curcumin have been reported and
their antibacterial activity against three various strains of
Streptococcus pneumoniae has been investigated. These
glucoside derivatives showed better results than curcumin
* Peyman Salehi
p-salehi@sbu.ac.ir
1
Department of Phytochemistry, Medicinal Plants and Drugs
Research Institute, Shahid Beheshti University, G. C., Evin,
Tehran 1983963113, Iran
2
Institute of Biochemistry and Biophysics (IBB), University
of Tehran, Tehran 1417614418, Iran
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
Scheme 1 Synthesis of propargylated phenolic aldehydes
Fig. 1 Important sites of curcumin for modification
even on the penicillin-resistant species [20]. Quinoline
derivatives of tetrahydrocurcumin were synthesized and
showed better antibacterial properties than tetrahydrocur-
cumin against Gram-positive and Gram-negative bacteria
[21]. 3,4-Dihydropyrimidinone derivatives of curcumin
have also been synthesized and their biological properties
have been evaluated against five bacterial strains and some
of these derivatives had lower MICs than ampicillin as a
commercial drug [22]. A number of Knoevenagel deriva-
tives of curcumin with various aldehydes have already
been synthesized in 2012 by Sahu et al. [23], which most
of them were more effective than curcumin against fungal
strains such as Aspergillus niger and Aspergillus fumiga-
tus and some bacteria such as Staphylococcus aureus and
Escherichia coli.
Results and discussion
Chemistry
Because of the diverse biological and pharmacological
properties of curcumin and its Knoevenagel derivatives
and valuable features of 1,2,3-triazole ring system, we
decided to synthesize new triazole tethered curcumin
derivatives using different propargyl ethers of benzalde-
hyde in the Knoevenagel reaction of the middle carbon of
curcumin followed by the Huisgen 1,3-dipolar cycloaddi-
tion. To achieve this goal, ortho, meta and para hydrox-
ylbenzaldehydes were propargylated using propargyl bro-
mide in the presence of potassium carbonate to give the
corresponding propargyl ethers 4a–4c (Scheme 1) [40]
(Scheme 2).
1,2,3-Triazole ring is one of the most important groups
in organic and medicinal chemistry. This moiety is a syn-
thetic group that does not exist in nature and in combi-
nation with different molecules shows diverse biological
activities [24]. 1,2,3-Triazoles show various pharmacolog-
ical properties such as: anticancer [25, 26], anti-parasitic
[24], antimicrobial [26, 27], anti-HIV [26, 28], antiviral
[24, 29] and anti-inflammatory [24, 30].
Our strategy for the synthesis of target molecules was
based on the reaction of terminal acetylene group of 5a–5c
with azides in the presence of Cu (I) (Scheme 3). There-
fore, different aryl and benzyl azides with different sub-
stituents were synthesized (Fig. 2) [41].
By the reaction of these azides with 5a–5c, a library
of novel 1,2,3-triazole tethered curcumin derivatives was
obtained (Scheme 3). The results of copper catalyzed
Huisgen 1,3-dipolar cycloaddition for the synthesis of
7a–7y are shown in Table 1. These derivatives were syn-
thesized using various azides with electron donating sub-
stituents such as methyl and ethyl groups (entries 3, 5, ,14
and 21), electron withdrawing nitro group (entries 11, 18
and 25) and halogen substituents such as chloro (entries
8, 16 and 23), bromo (entries 2, 10, 13, 15, 20 and 22) and
fluoro (entries 1, 12, and 19) groups. All of the click reac-
tions were done at less than 30 min with good to excellent
yields.
1,2,3-Triazoles have special chemical and structural
features [31]. They are stable under various conditions
such as acidic and basic hydrolysis, and also oxidative
and reductive statuses due to their high aromatic stabili-
zation [32]. Several methods have been developed for the
synthesis of this building block [31]. Huisgen 1,3-dipolar
cycloaddition is a type of click reaction between a terminal
alkyne and azides for making triazole rings [33, 34]. Fokin
and Sharpless in 2002 introduced a method for regioselec-
tive synthesis of 1,4-disubstituted-1,2,3-triazoles in the
presence of copper(Ι) as catalyst [35]. Actually, Cu(I)-cat-
alyzed azide-alkyne cycloaddition (CuAAC) is the most
important example of click chemistry [36].
In continuation of our studies on the synthesis of nat-
ural products tethered triazole ring and their biological
activities [37–39], here we report the synthesis of new
Knoevenagel derivatives of curcumin containing 1,2,3-tri-
azole ring and investigation of their antimicrobial activity
together with QSAR studies.
Antibacterial assay
All of the new synthesized derivatives were evaluated for
their antibacterial properties. The antibacterial activities
were investigated against Staphylococcus aureus (ATCC
25923), Bacillus subtilis (ATCC 645), Escherichia coli
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Journal of the Iranian Chemical Society
Scheme 2 Knoevenagel reac-
tion of curcumin with propargyl
ethers of phenolic benzalde-
hydes
Scheme 3 Huisgen 1,3-dipolar
cycloaddition between Knoev-
enagel derivatives of curcumin
and azides
Fig. 2 Structures of the synthesized azides
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Journal of the Iranian Chemical Society
Table 1 Synthesis of 1,2,3-triazole tethered Knoevenagel derivatives
Table 2 Antibacterial activities of the synthesized derivatives
of curcumin
MIC (µM)
Entry
Products
Alkyne
Azide
Yield (%)
Entry Products
S. aureus B. subtilis E. coli P. aeruginosa
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7f
7g
7h
7i
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5b
5b
5b
5b
5b
5b
5b
5c
5c
5c
5c
5c
5c
5c
6a
6b
6c
6d
6e
6f
91
88
90
89
97
88
87
93
84
81
97
83
86
85
94
89
89
92
82
84
88
86
86
89
91
1
2
3
4
5
6
7
8
Curcumin
5a
43.43
125.36
62.68
62.68
193.45
88.57
97.31
49.75
48.65
99.50
50.82
11.45
23.20
90.32
23.72
96.72
88.57
48.65
90.32
91.62
50.82
47.43
48.36
44.29
48.65
90.32
45.81
50.82
47.43
2.20
86.87
125.36
62.68
347.47 347.47
250.72 250.72
250.72 501.44
125.36 250.72
193.48 386.90
177.14 354.29
97.31 194.61
99.50 397.99
97.31 389.23
198.99 397.99
101.64 406.57
91.62 366.47
92.79 371.17
180.65 180.65
94.86 379.45
193.45 386.90
88.57 354.29
97.31 389.23
90.32 180.65
183.24 366.48
101.64 406.57
94.86 379.45
96.72 386.90
88.57 177.14
97.31 389.23
90.32 361.30
91.62 366.48
101.64 406.57
94.86 189.73
17.64 141.14
72.12 1150.01
5b
5c
31.40
7a
386.90
354.29
389.23
198.99
194.61
397.99
406.57
366.47
371.17
361.30
189.73
386.90
177.14
194.61
180.65
183.24
203.28
189.73
386.90
177.14
194.61
361.30
183.24
203.28
379.45
8.82
7b
6g
6h
6i
7c
7d
9
9
7e
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
7j
7k
7l
6j
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
7f
6k
6a
6b
6c
6j
7g
7h
7m
7n
7o
7p
7q
7r
7s
7i
7j
7k
6h
6g
6k
6a
6b
6c
6j
6 h
6 g
6 k
7l
7m
7n
7o
7t
7p
7u
7v
7w
7x
7y
7q
7r
7s
7t
7u
7v
(ATCC 25922) and Pseudomonas aeruginosa (ATCC
85327). The results of the in vitro tests are summarized
in Table 2. Among these products, compounds 7h, 7i and
7k showed MICs of 11.45, 23.20 and 23.72 µM against S.
aureus, respectively (Table 2, entries 12, 13 and 15), that
7h had a stronger activity than tetracycline (Table 2, entry
31). In the case of E. coli all of the synthesized compounds
showed better MIC values than curcumin. In addition, com-
pounds 5a 5c, 7c, 7j, 7o, 7t and 7y showed better MICs than
curcumin against P .aeruginosa in the range of 141–250 µM
(Table 2, entries 2, 4, 7, 14 19, 24 and 29). P .aeruginosa is
one of the most problematic drug resistant pathogens among
the Gram-negative bacteria [42]. The MIC value of tetracy-
cline against P. aeruginosa was about 1150 µM (Table 2,
entry 31), whereas all of the semisynthetic derivatives of
curcumin in this study showed lower MICs than tetracycline.
In addition, 7t showed an activity in the range of cefixime.
7w
7x
7y
Cefixime
Tetracycline 18.05
4.53
than curcumin (173.73 µM). Among the para-substituted
products 7g and 7k showed antifungal activities better than
the parent compound. Compounds 7n–7r showed MICs
between 90 and 101 µM and compounds 7t, 7u and 7x
showed MICs of 88.57, 97.31 and 101.64 µM, respectively.
Among these derivatives, the synthesized compounds from
5b which was the meta derivative showed the best results.
QSAR model
Based on the number of molecules in the training set (23 mole-
cules), four descriptors selected to construct the QSAR models.
The statistical parameters of constructed MLR (multiple linear
regression) model by selected descriptors are listed in Table 4.
Equations 1, 2, 3, 4 and 5 shows the specifications of
the obtained MLR model which was made by selected
Antifungal activity
Antifungal in vitro assay was done against Candida albicans
(ATCC 10231). The results are demonstrated in Table 3.
Compound 5a showed MIC of 125.36 µM that was better
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Journal of the Iranian Chemical Society
Table 3 Antifungal activity of the synthesized derivatives against C.
compound against S. aureus), 45.81 and 91.62, respectively.
These results demonstrate that by increasing the number of
Cl atoms the MIC against S. aureus decreases. Therefore,
compounds with C1 atom would be preferred for S. aureus.
The nF descriptor in the MLR model for predicting MIC
against B. subtilis is the number of F atom counts in the
compound. For the compounds 7a, 7l and 7s with F atoms
the value of MIC was 386.9. In addition, for compound 5c
(the most active compound against B. subtilis) without F
atoms the value of MIC was 31.4. Therefore, by increasing
the number of F atoms the MIC against B. subtilis increases.
In the case of P. aeruginosa number of Br atom counts
in the compound (nBr) represents a significant effect on the
inhibitory activity. For the compounds 7t, 7j, 7o, 7b, 7m and
7v with Br atoms the value of MIC was 177.14 (the most
active compound against P. aeruginosa), 180.65, 180.65,
354.29, 354.29 and 361.3, respectively. In addition, for com-
pound 5b (the most inactive compound against P. aerugi-
nosa) without Br atom the value of MIC was 501.44. Hence,
it is revealed that by increasing the number of Br atom counts
in the compound, the inhibitory activity increases against P.
aeruginosa. The predicted and experimental values of MIC
are shown in Table 5. In addition, these results were plotted
versus their experimental values, shown in Fig. 3, 4, 5, 6,
and 7 for S. aureus, B. subtilis, E. coli, P. aeruginosa, and C.
albicans, respectively. These figures show a good agreement
between the experimental results and the predicted values.
albicans
Entry Products MIC (µM) Entry Products
MIC (µM)
1
2
3
4
5
6
7
8
5a
5b
5c
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
125.36
250.72
250.72
193.49
177.14
194.61
198.99
194.61
397.99
101.64
366.47
185.58
180.65
94.86
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
7m
7n
7o
7p
7q
7r
7s
177.14
97.31
90.32
91.62
101.64
94.86
193.45
88.57
97.31
361.30
366.48
101.64
189.73
7t
9
7u
7v
7w
7x
7y
10
11
12
13
14
15
Curcumin 173.73
Nystatin 8.64
193.45
Table 4 Statistical parameters of the MLR models for the antibacte-
rial and antifungal activity
S. aureus B. subtilis E. coli P. aerugi-
nosa
C. albicans
Rtrn
RMSEtrn 33.198
Rtest 0.750
RMSEtest 49.841
0.814
0.755
159.724
0.755
0.911
44.270 123.775
0.672 0.851
51.234 32.865
0.776
0.811
106.117
0.854
68.704
75.056
Conclusions
descriptors for S. aureus, B. subtilis, E. coli, P. aeruginosa
and C. albicans, respectively:
A new series of 25 triazole tethered derivatives of cur-
cumin were synthesized by the Knoevenagel reaction of
(1)
MIC = 297.716 − 5.908 (RDF50s) − 35.297(ATSC3e) − 25.370(nCl) + 1.862 (RDF100m)
MIC = 507.138 + 2.418(RDF110u) + 2.8516 (VR3_Dzp) + 113.124(nF) + 11.503(RDF50u)
MIC = 321.917 − 3.974(RDF80u) − 2.750(ATSC6s) − 14.117(RDF35m) + 1.838(RDF90m)
MIC = 8874.874 − 93.284(nBr) − 7.173(TDB9i) − 8.325(RDF100m) + 14.184(L1u)
(2)
(3)
(4)
(5)
MIC = 146.143 − 8.055(RDF155u) + 15.880(RDF125m) − 13.587(RDF120m) + 7.148 (RDF100m).
The nCl descriptor in the QSAR model for predicting
MIC against S. aureus is the number of Cl atom counts
in the compound. For the compounds 7h, 7w and 7p with
2 Cl atoms the value of MIC was 11.45 (the most active
middle carbon of curcumin with propargylated hydroxyl
aldehydes followed by Huisgen alkyne-azide 1,3-dipolar
cycloaddition. Most of the synthesized compounds showed
a better antimicrobial activity against Gram-positive and
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Journal of the Iranian Chemical Society
Table 5 Compounds list, observed, and predicted MIC values
Bacteria species
Antifungal test
S. aureus
B. subtilis
E. coli
P. aeruginosa
C. albicans
MIC (µM)
Predicted
MIC (µM)
Predicted
MIC (µM)
Predicted
MIC (µM)
Predicted
MIC (µM)
Predicted
5a
5b
5c
7b
7c
7d
7e
7g
7h
7i
7j
7l
7m
7n
7o
7q
7r
7s
7t
7v
7w
7x
7y
*7a
*7f
*7k
*7p
*7u
125.36
62.68
62.68
88.57
97.31
49.75
48.65
50.82
11.45
23.20
90.32
96.72
88.57
48.65
90.32
50.82
47.43
48.36
44.29
90.32
45.81
50.82
47.43
193.45
99.50
23.72
91.62
48.65
116.71
53.08
44.08
85.02
69.38
74.73
69.02
56.57
28.07
20.43
82.34
73.78
78.20
52.08
85.35
60.87
46.19
80.61
69.11
82.16
29.19
52.98
50.41
96.43
91.75
45.09
43.37
61.44
125.36
62.68
31.40
88.45
80.52
52.73
250.72
250.72
125.36
177.14
97.31
99.50
97.31
101.64
91.62
92.79
180.65
193.45
88.57
97.31
90.32
101.64
94.86
96.72
88.57
90.32
91.62
101.64
94.86
193.48
198.99
94.86
183.24
97.31
254.24
248.99
118.32
159.77
103.20
137.06
90.31
250.72
501.44
250.72
354.29
194.61
397.99
389.23
406.57
366.47
371.17
180.65
386.90
354.29
389.23
180.65
406.57
379.45
386.90
177.14
361.30
366.48
406.57
189.73
386.90
397.99
379.45
366.48
389.23
263.58
460.48
309.69
310.74
157.84
419.02
369.81
405.20
368.29
307.18
256.95
391.45
261.61
385.55
251.29
367.82
330.74
409.31
275.64
252.08
365.60
406.55
322.66
401.90
428.31
334.00
329.28
360.82
125.36
250.72
250.72
177.14
194.61
198.99
194.61
101.64
366.47
185.58
180.65
193.45
177.14
97.31
90.32
101.64
94.86
193.45
88.57
361.30
366.48
101.64
189.73
193.49
397.99
94.86
166.71
221.32
175.33
242.04
209.86
188.80
244.40
170.85
325.27
100.44
217.91
144.96
117.95
101.75
74.46
135.44
138.89
207.81
126.61
267.37
359.04
177.07
168.12
194.80
343.34
131.75
238.13
145.81
354.29
389.23
198.99
194.61
406.57
366.47
371.17
361.30
386.90
177.14
194.61
180.65
203.28
189.73
386.90
177.14
361.30
183.24
203.28
379.45
386.90
397.99
189.73
183.24
194.61
265.81
317.03
245.51
244.91
257.01
234.18
415.73
295.64
391.89
264.15
236.07
280.68
261.31
254.25
381.91
272.79
275.03
233.24
265.50
271.35
377.64
273.18
251.40
220.52
247.02
99.55
95.86
105.26
125.61
160.77
121.35
77.82
106.68
83.23
76.42
123.26
103.82
105.20
101.70
100.34
95.87
189.61
107.92
72.91
117.41
96.59
91.62
97.31
*Referring to the compounds in test set
B. subtilis
500
400
300
200
100
200
S. aureus
150
100
50
0
0
0
100
200
300
400
500
0
20 40 60 80 100 120 140 160 180 200
Experimental MIC
Experimental MIC
Fig. 4 Plot of predicted MIC versus observed values for B. subtilis
Fig. 3 Plot of predicted MIC versus observed values for S. aureus
using QSAR model
using QSAR mode
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Journal of the Iranian Chemical Society
five QSAR models were developed and the results showed
a good agreement between predicted and observed activi-
ties. Therefore, curcumin and its derivatives can be consid-
ered as potent candidates for antimicrobial studies.
E. coli
300
250
200
150
100
50
Experimental
General
50
100
150
200
250
300
All starting materials were obtained from Merck, Sigma and
Acros companies and were used without further purifica-
tion. Melting points were measured on a Branstead/Elec-
trothermal 9200 apparatus and were not corrected. 1HNMR
and 13CNMR spectra were recorded on a Bruker Avance
III spectrometers at in 400 and 100 MHz, respectively in
DMSO-d6 as solvent. HRESI-MS spectra in positive ion
modes were recorded on a Bruker micro-TOFESI-MS sys-
tem with a scan range of m/z 200–1500. MS calibration was
performed using a reference solution of sodium formate
0.1% in isopropanol–water (1:1) containing 5 mM sodium
hydroxide. The typical mass accuracy was 3 ppm. The
HyStar 3.0 software (Bruker Daltonics) was used for data
acquisition and processing.
Experimental MIC
Fig. 5 Plot of predicted MIC versus observed values for E. coli using
QSAR model
P. aeruginosa
600
500
400
300
200
100
General procedure for the synthesis of Knoevenagel
derivatives 5a–5c
100
200
300
400
500
600
Experimental MIC
To a solution of 3.68 g (10 mmol) curcumin in chloroform
(20 ml) and 1.76 g (11 mmol) phenyl propargyl ethers, in
a round-bottomed flask, 10 µl of piperidine diluting in 2 ml
chloroform, was added dropwise. The mixture was refluxed
for 48 h. After completion of reaction monitoring by TLC,
50 ml water was added to reaction mixture then the mixture
was extracted with chloroform (2×75 ml). After drying the
combined organic layers over anhydrous sodium sulfate, sol-
vent was evaporated under reduced pressure. The residue
was dissolved in ethanol and the pure product precipitated
in 24 h.
Fig. 6 Plot of predicted MIC versus observed values for P. aerugi-
nosa using QSAR model
C. albicans
400
350
300
250
200
150
100
50
General procedure for the synthesis of 1,2,3‑triazole
tethered Knoevenagel derivatives of curcumin
7a–7y
0
0
100
200
300
400
500
Synthesis of the target compounds 7a–7y was carried out
by the reaction of Knoevenagel derivatives of curcumin
5a–5c (0.5 mmol) and various azides (0.55 mmol) in the
presence of sodium ascorbate (0.2 mmol) and copper sulfate
(0.1 mmol) in methanol (5 ml) at room temperature for less
than 30 min to give 1,4-disubstituted 1,2,3-triazoles. The
progress of reaction was monitored by TLC. After comple-
tion of the reaction, 30 ml saturated aqueous solution of
EDTA was added to reaction mixture and extracted with
Experimental MIC
Fig. 7 Plot of predicted MIC versus observed values for C. albicans
using QSAR model
Gram-negative bacteria and a fungus in comparison to cur-
cumin. To investigate the relationship between structure
and antimicrobial activities of the synthesized compounds,
1 3

Journal of the Iranian Chemical Society
ethyl acetate (2×75 ml). The organic layers were combined
and dried over anhydrous sodium sulfate. Solvent was
removed under reduced pressure. Final purification was
performed using preparative thin layer chromatography or
recrystallization in dichloromethane to give 82–97% yields.
(1E,6E)-1,7-Bis(4-hydroxy-3-methoxyphenyl)-4-(4-
(prop-2-yn-1-yloxy)benzylidene)hepta-1,6-diene-3,5-di-
one 5a (C31H26O7), brick red powder, m. p. :103–105 °C
decompose.
139.55, 135.81, 132.66, 132.18, 130.71, 126.76, 126.27,
125.40, 125.34, 124.58, 124.18, 121.96, 118.50, 116.26,
116.19, 115.58, 112.63, 112.00, 61.62, 56.27, 56.09, 52.58.
ESI-HRMS (m/z): 744.1350 (M + Na), Anal. Calc. for
C38H32BrN3NaO7: 744.1316. Error: 4.6 ppm.
(1E, 6E)-4-(4-((1-(4-Methylbenzyl)-1H-1,2,3-triazol-
4-yl)methoxy)benzylidene)-1,7-bis(4-hydroxy-3-methoxy-
phenyl 7c(C39H35N3O7), orange powder, m. p.: 77–79 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H), 8.00 (s,
1H), 7.60 (d, J = 15.3 Hz, 1H), 7.57–7.50 (m, 3H), 7.43
(d, J = 1.8 Hz, 1H), 7.39 (d, J = 16.1 Hz, 1H), 7.30–7.26
(m, 2H), 7.22 (d, J=8.1 Hz, 2H), 7.18 (d, J=8.1 Hz, 2H),
7.12–7.07 (m, 3H), 6.91 (d, J = 16.2 Hz, 1H), 6.86 (d,
J=8.2 Hz, 1H), 6.78 (d, J=8.2 Hz, 1H), 5.55 (s, 2H,CH2),
5.17 (s, 2H,CH2), 3.87 (s, 3H,OCH3), 3.80 (s, 3H,OCH3),
2.28 (s, 3H,CH3). 13C NMR (100 MHz, DMSO-d6) δ
198.56, 188.26, 160.19, 150.98, 150.52, 148.56, 148.47,
147.32, 144.57, 142.97, 139.65, 138.03, 133.40, 132.68,
129.77, 128.51, 126.72, 126.49, 125.66, 125.16, 124.80,
124.47, 124.10, 118.66, 116.22, 116.13, 115.59, 112.67,
112.07, 61.64, 56.29, 56.11, 53.15, 21.14. ESI-HRMS
(m/z): 680.2387 (M+Na), Anal. Calc. for C39H35N3O7Na:
680.2367. Error: 2.9 ppm.
1H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H, H-C=C),
7.59 (d, J=15.3 Hz, 1H, olefin), 7.56–7.50 (m, 3H, aromatic
and olefin overlap), 7.42 (d, J=1.9 Hz, 1H,aromatic), 7.39
(d, J = 16.2 Hz, 1H, olefin), 7.29–7.26(m, 2H, aromatic),
7.10 (dd, J = 8.3 and 1.8 Hz, 1H, aromatic), 7.06–7.04
(m, 2H, aromatic), 6.90(d, J = 16.1 Hz, 1H, olefin), 6.85
(d, J=8.2 Hz, 1H,aromatic), 6.76 (d, J =8.2 Hz, 1H, aro-
matic),4.85 (d, J =2.3 Hz, 1H, CH2), 3.86 (s, 3H, OCH3),
3.79 (s, 3H, OCH3), 3.60 (t, J = 2.3 Hz, 1H). 13C NMR
(100 MHz, DMSO-d6) δ 198.50, 188.26, 159.27, 151.62,
151.01, 148.69, 148.57, 147.50, 144.74, 139.92, 139.47,
132.57, 127.14, 126.23, 125.30, 124.64, 124.56, 124.25,
118.47, 116.31, 116.25, 115.69, 112.59, 112.00, 79.28,
79.04, 56.27, 56.08, 56.02. ESI-HRMS (m/z): 533.1578
(M + Na), Anal. Calc. for C31H26NaO7: 533.1571. Error:
1.6 ppm.
(1E, 6E)-4-(4-((1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy)
benzylidene)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-
1,6-diene-3,5-dione 7d (C38H33N3O7), dark orange powder,
m. p.: 90–92 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.30 (s,
1H), 8.00 (s, 1H), 7.59 (d, J=15.3 Hz, 1H), 7.56–7.51 (m,
3H), 7.43 (d, J=1.8 Hz, 1H), 7.41–7.27 (m, 8H), 7.12– 7.08
(m, 3H), 6.91 (d, J=16.2 Hz, 1H), 6.85 (d, J=8.2 Hz, 1H),
6.77 (d, J=8.2 Hz, 1H), 5.61 (s, 2H), 5.18 (s, 2H), 3.86 (s,
3H), 3.80 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 198.59,
188.28, 160.19, 150.85, 150.42, 148.53, 148.45, 147.31,
144.56, 143.03, 139.70, 139.64, 136.41, 132.69, 129.24,
128.65, 128.44, 126.72, 126.56, 125.75, 125.33, 124.86,
124.44, 124.09, 118.69, 116.21, 116.13, 115.67, 115.60,
112.66, 112.08, 61.64, 56.30, 56.12, 53.34. ESI-HRMS
(m/z): 666.2227 (M+Na), Anal. Calc. for C38H33N3O7Na:
666.2211. Error: 2.4 ppm.
(1E,6E)-4-(4-((1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)
methoxy)benzylidene)-1,7-bis(4-hydroxy-3-methoxyphe-
nyl)hepta-1,6-diene-3,5-dione 7a (C38H32FN3O7), orange
1
powder, m. p.:107–109 °C. H NMR (400 MHz, DMSO-
d6) δ 8.29 (s, 1H), 8.00 (s, 1H), 7.59 (d, J=15.4 Hz, 1H),
7.49–7.56 (m, 3H), 7.44–7.34 (m, 4H), 7.32–7.17 (m, 4H),
7.10 (m, 3H), 6.91 (d, J=16.2 Hz, 1H), 6.85 (d, J=8.2 Hz,
1H), 6.77 (d, J = 8.2 Hz, 1H), 5.60 (s, 2H, CH2), 5.17 (s,
2H, CH2), 3.87(s, 3H, OCH3), 3.80(s, 3H, OCH3), 13C NMR
(100 MHz, DMSO-d6) δ 198.58, 188.28, 163.60, 161.17,
160.19, 150.86, 150.42, 148.54, 148.45, 147.31, 144.56,
143.05, 139.70, 139.65, 132.68, 132.64, 130.85, 130.77,
126.73, 126.55, 125.73, 125.25, 124.85, 124.44, 124.09,
118.69, 116.19, 116.13, 115.97, 115.58, 112.65, 112.07,
61.63, 56.29, 56.11, 52.54. ESI-HRMS (m/z): 684.2132
(M+Na), Anal. Calc. for C38H32FN3NaO7: 684.2116. Error:
2.3 ppm.
(1E, 6E)-4-(4-((1-(4-Ethylphenyl)-1H-1,2,3-triazol-4-yl)
methoxy)benzylidene)-1,7-bis(4-hydroxy-3-methoxyphenyl)
hepta-1,6-diene-3,5-dione 7e (C39H35N3O7), yellow pow-
1
(1E, 6E)-4-(4-((1-(4-Bromobenzyl)-1H-1,2,3-triazol-
4-yl)methoxy)benzylidene)-1,7-bis(4-hydroxy-3-meth-
oxyphenyl)hepta-1,6-diene-3,5-dione 7b (C38H32BrN3O7),
der, m. p.: 146–148 °C. H NMR (400 MHz, DMSO-d6)
δ 8.91 (s, 1H), 7.98 (s, 1H), 7.83–7.76 (m, 2H),7.60–7.42
(m, 6H), 7.38 (d, J = 16.2 Hz, 2H), 7.28–7.25 (m, 2H),
7.15 (d, J = 9.0 Hz, 2H), 7.08 (dd, J = 8.3, 1.8 Hz, 1H),
6.87 (d, J=16.1 Hz, 1H), 6.82 (d, J=8.2 Hz, 1H), 6.73 (d,
J = 8.2 Hz, 1H), 5.27 (s, 2H), 3.85 (s, 3H), 3.78 (s, 3H),
2.69 (q, J=7.6 Hz, 2H), 1.23 (t, J=7.6 Hz, 3H). 13C NMR
(100 MHz, DMSO-d6) δ 198.43, 188.14, 160.11, 152.24,
151.44, 148.80, 148.64, 147.50, 145.13, 144.71, 143.74,
139.85, 139.40, 134.92, 132.69, 129.56, 126.91, 125.96,
124.91, 124.78, 124.32, 124.27, 123.45, 120.66, 118.30,
1
orange powder, m. p. :89–91 °C. H NMR (400 MHz,
DMSO-d6) δ 8.30 (s, 1H), 7.98 (s, 1H), 7.62–7.49 (m,
6H), 7.41 (d, J = 1.8 Hz, 1H), 7.38 (d, J = 16.1 Hz, 1H),
7.29–7.25 (m, 4H), 7.08–7.11 (m, 3H), 6.89 (d, J=16.1 Hz,
1H), 6.84 (d, J=8.2 Hz, 1H), 6.75 (d, J=8.2 Hz, 1H), 5.60
(s, 2H), 5.17 (s, 2H), 3.86 (s, 3H), 3.79 (s, 3H). 13C NMR
(100 MHz, DMSO-d6) δ 198.50, 188.20, 160.15, 151.48,
150.87, 148.65, 148.53, 147.39, 144.61, 143.07, 139.70,
1 3

Journal of the Iranian Chemical Society
116.34, 116.29, 115.61, 112.57, 111.93, 60.66, 56.24, 56.05,
28.16, 15.89. ESI-HRMS (m/z): 680.2378(M+Na), Anal.
Calc. for C39H35N3O7Na: 680.2367. Error: 1.7 ppm.
(1E, 6E)-4-(4-((1-p-Tolyl-1H-1,2,3-triazol-4-yl)meth-
oxy)benzylidene)-1,7-bis(4-hydroxy-3-methoxyphenyl)
hepta-1,6-diene-3,5-dione 7f (C38H33N3O7), brick red
powder, m. p.: 112–114 °C. 1H NMR (400 MHz, DMSO-
d6) δ 8.91 (s, 1H), 8.01 (s, 1H), 7.78 (d, J = 8.5 Hz, 2H),
7.59 (d, J = 15.2 Hz, 1H), 7.57–7.51 (m, 3H),7.44–7.37
(m, 4H). 7.29 (d, J=1.4 Hz, 1H), 7.27 (d, J=1.8 Hz, 1H),
7.15 (d, J = 9.0 Hz, 2H), 7.10 (dd, J = 8.3, 1.8 Hz, 1H),
6.91 (d, J=16.2 Hz, 1H), 6.86 (d, J=8.2 Hz, 1H), 6.78 (d,
J = 8.2 Hz, 1H), 5.27 (s, 2H), 3.87 (s, 3H), 3.80 (s, 3H),
2.39 (s, 3H).
(M + Na), Anal. Calc. for C37H29Cl2N3O7Na: 720.1275.
Error: 2.9 ppm.
(1E, 6E)-4-(4-((1-(3,4-Dimethoxyphenyl)-1H-1,2,3-tria-
zol-4-yl)methoxy)benzylidene)-1,7-bis(4-hydroxy-3-meth-
oxyphenyl)hepta-1,6-diene-3,5-dione 7i (C39H35N3O9), brick
red powder, m. p.: 143–145 °C. 1H NMR (400 MHz, DMSO-
d6) δ 8.90 (s, 1H), 7.99 (s, 1H), 7.61–7.46 (m,5H), 7.43–7.35
(m, 3H), 7.30–7.25 (m, 2H), 7.14 (dd, J=8.9, 3.2 Hz, 3H).,
7.09 (dd, J = 8.3, 1.8 Hz, 1H), 6.89 (d, J = 16.1 Hz, 1H),
6.83 (d, J = 8.2 Hz, 1H), 6.74 (d, J = 8.2 Hz, 1H), 5.21
(s, 2H), 3.86 (s, 3H), 3.86 (s, 3H), 3.83 (s, 3H), 3.79 (s,
3H). 13C NMR (100 MHz, DMSO-d6) δ 198.46, 188.19,
160.14, 151.62, 150.97, 149.77, 149.42, 148.68, 148.55,
147.41, 144.63, 143.60, 139.78, 139.51, 132.69, 130.41,
126.87, 126.21, 125.26, 124.62, 124.50, 124.21, 123.61,
118.47, 116.27, 116.21, 115.61, 112.74, 112.63, 112.42,
112.01, 105.21, 61.66, 56.33, 56.25, 56.08. ESI-HRMS
(m/z): 712.2300 (M+Na), Anal. Calc. for C39H35N3O9Na:
712.2266. Error: 4.8 ppm.
13C NMR (100 MHz, DMSO-d6) δ 198.54, 188.27,
160.14, 150.99, 150.54, 148.55, 148.47, 147.32, 144.58,
143.74, 139.71, 139.66, 138.91, 134.75, 132.71, 130.71,
126.85, 126.48, 125.65, 124.79, 124.45, 124.11, 123.41,
120.51, 118.65, 116.22, 116.14, 115.63, 112.65, 112.08,
61.59, 56.30, 56.11, 21.03. ESI-HRMS (m/z): 666.2216
(M+Na), Anal. Calc. for C38H33N3O7Na: 666.2211. Error:
0.7 ppm.
(1E, 6E)-4-(4-((1-(4-Bromophenyl)-1H-1,2,3-triazol-
4-yl)methoxy)benzylidene)-1,7-bis(4-hydroxy-3-meth-
oxyphenyl)hepta-1,6-diene-3,5-dione 7j (C37H30BrN3O7),
1
(1E, 6E)-4-(4-((1-Phenyl-1H-1,2,3-triazol-4-yl)meth-
oxy)benzylidene)-1,7-bis(4-hydroxy-3-methoxyphenyl)
hepta-1,6-diene-3,5-dione 7g (C37H31N3O7) yellow pow-
brick red powder, m. p.: 130–133 °C decompose. H
NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.02 (s, 1H),
7.94–7.79 (m, 5H), 7.62–7.53 (m, 3H), 7.44 (d, J=1.8 Hz,
1H), 7.40 (d, J = 16.1 Hz, 1H), 7.32–7.26 (m, 2H), 7.15
(d, J = 9.0 Hz, 2H), 7.11 (dd, J = 8.3, 1.7 Hz, 1H), 6.92
(d, J = 16.2 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 6.78 (d,
1
der, m. p.: 112–114 °C decompose. H NMR (400 MHz,
DMSO-d6) δ 8.97 (s, 1H), 8.00 (s, 1H), 7.94–7.88 (m, 2H),
7.65–7.49 (m, 7H), 7.44–7.36 (m, 2H), 7.30–7.26 (m, 2H),
7.16 (d, J = 8.9 Hz, 2H), 7.10 (dd, J = 8.3, 1.8 Hz, 1H),
6.91 (d, J=16.2 Hz, 1H), 6.85 (d, J=8.2 Hz, 1H), 6.76 (d,
J = 8.2 Hz, 1H), 5.28 (s, 2H), 3.86 (s, 3H), 3.79 (s, 3H).
13C NMR (100 MHz, DMSO-d6) δ 198.53, 188.26, 160.14,
151.07, 150.58, 148.57, 148.48, 147.35, 144.60, 143.87,
139.75, 139.64, 136.99, 132.71, 130.38, 129.27, 126.87,
126.46, 125.62, 124.77, 124.50, 124.12, 123.55, 120.66,
118.64, 116.23, 116.15, 115.64, 112.67, 112.08, 61.59,
56.29, 56.12. ESI-HRMS (m/z): 652.2086 (M+Na), Anal.
Calc. for C37H31N3O7Na: 652.2054. Error: 4.8 ppm.
J=8.2 Hz, 1H), 5.28 (s,2H), 3.87 (s, 3H), 3.80 (s, 3H). 13
C
NMR (100 MHz, DMSO-d6) δ 198.53, 188.27, 160.10,
150.73, 150.33, 148.50, 148.42, 147.27, 144.54, 144.06,
139.71, 136.18, 133.27, 132.70, 126.87, 126.58, 125.79,
124.89, 124.40, 124.06, 123.58, 122.57, 121.95, 118.71,
116.18, 116.09, 115.71, 115.63, 112.68, 112.10, 61.54,
56.31, 56.13. ESI-HRMS (m/z): 730.1188 (M+Na), Anal.
Calc. for C37H30BrN3O7Na: 730.1159. Error: 3.9 ppm.
(1E, 6E)-4-(4-((1-(4-Nitrophenyl)-1H-1,2,3-triazol-4-yl)
methoxy)benzylidene)-1,7-bis(4-hydroxy-3-methoxyphenyl)
hepta-1,6-diene-3,5-dione 7k (C37H30N4O9), yellow pow-
(1E, 6E)-4-(4-((1-(3,4-Dichlorophenyl)-1H-1,2,3-triazol-
4-yl)methoxy)benzylidene)-1,7-bis(4-hydroxy-3-methoxy-
phenyl)hepta-1,6-diene-3,5-dione 7h (C37H29Cl2N3O7),
brick red powder, m. p.: 124–126 °C. 1H NMR (400 MHz,
DMSO-d6) δ 9.06 (s, 1H), 8.28 (d, J=2.5 Hz, 1H), 8.03–7.85
(m, 3H), 7.61–7.49 (m, 4H), 7.42–7.36 (m, 2H), 7.30–7.26
(m, 2H), 7.14 (d, J=9.0 Hz, 2H), 7.09 (dd, J=8.3, 1.8 Hz,
1H), 6.90 (d, J = 16.1 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H),
6.75 (d, J=8.2 Hz, 1H), 5.29 (s,2H), 3.86 (s, 3H), 3.79 (s,
3H). 13C NMR (100 MHz, DMSO-d6) δ 198.48, 188.19,
160.04, 151.53, 150.90, 148.66, 148.53, 147.42, 144.65,
144.19, 139.80, 139.52, 136.45, 132.84, 132.71, 132.20,
131.60, 126.93, 126.26, 125.33, 124.58, 124.18, 123.72,
122.28, 120.56, 118.50, 116.27, 116.20, 115.61, 112.61,
112.00, 61.52, 56.26, 56.08. ESI-HRMS (m/z): 720.1296
1
der, m. p.: 147–149 °C decompose. H NMR (400 MHz,
DMSO-d6) δ 9.18 (s, 1H), 8.47 (d, J=9.1 Hz, 2H), 8.24 (d,
J=9.0 Hz, 2H), 8.02 (s, 1H), 7.63–7.52 (m, 4H), 7.45–7.27
(m, 4H), 7.16 (d, J=8.9 Hz, 2H), 7.11 (d, J=7.7 Hz, 1H),
6.92 (d, J=16.2 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 6.78 (d,
J = 8.1 Hz, 1H), 5.32 (s, 2H), 3.87 (s, 3H), 3.80 (s, 3H).
13C NMR (100 MHz, DMSO-d6) δ 198.54, 188.28, 160.06,
150.49, 150.17, 148.44, 148.40, 147.23, 144.53, 141.19,
139.72, 132.71, 126.92, 126.68, 126.00, 125.94, 124.99,
124.35, 124.00, 123.95, 121.15, 118.77, 116.16, 116.08,
115.65, 112.67, 112.10, 61.48, 56.30, 56.14. ESI-HRMS
(m/z): 697.1918 (M+Na), Anal. Calc. for C37H30N4O9Na:
697.1905. Error: 1.9 ppm.
1 3

Journal of the Iranian Chemical Society
(1E, 6E)-4-(3-(Prop-2-ynyloxy)benzylidene)-1,7-bis(4-
hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione 5b
(C31H26O7), brick red powder, m. p.: 156–158 °C 1H NMR
(400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.62 (d, J=15.4 Hz,
1H), 7.54 (d, J = 15.4 Hz, 1H), 7.44 (d, J = 1.8 Hz, 1H),
7.41–7.34 (m, 1H), 7.31–7.27 (m, 1H), 7.20–7.15 (m, 1H),
7.10 (dd, J=8.3, 1.8 Hz, 1H), 7.07–7.02 (m, 1H), 6.90 (d,
J=16.2 Hz, 1H), 6.86 (d, J=8.2 Hz, 1H), 6.77 (d, J=8.2 Hz,
1H), 4.78 (d, J = 2.1 Hz, 1H), 3.86 (s, 1H), 3.80 (s, 1H),
3.57 (t, J = 2.1 Hz, 1H). 13C NMR (100 MHz, DMSO-d6)
δ 197.79, 188.46, 157.70, 150.96, 150.69, 148.56, 148.50,
147.62, 145.21, 142.22, 139.48, 135.58, 130.41, 126.41,
125.72, 124.79, 124.53, 124.28, 123.48, 118.62, 117.02,
116.79, 116.25, 116.15, 112.71, 112.07, 79.36, 78.90, 56.30,
56.13, 55.96. ESI-HRMS (m/z): 533.1588 (M+Na), Anal.
Calc. for C31H26O7Na: 533.1571. Error: 3.3 ppm.
(1E, 6E)-4-(3-((1-(4-Methylphenyl)-1H-1,2,3-triazol-
4-yl)methoxy)benzylidene)-1,7-bis(4-hydroxy-3-meth-
oxyphenyl)hepta-1,6-diene-3,5-dione 7n (C39H35N3O7),
brick red powder, m. p.: 124–126 °C. 1H NMR (400 MHz,
DMSO-d6) δ 8.24 (s, 1H), 7.98 (s, 1H), 7.61 (d, J=15.3 Hz,
1H), 7.51 (s, 1H), 7.42–7.37 (m, 1H), 7.35–7.31 (m, 1H),
7.30–7.25 (m, 2H), 7.25–7.18 (m, 4H), 7.17 (d, J=5.5 Hz,
1H), 7.14–7.10 (m, 1H), 7.07 (dd, J = 8.3, 2.1 Hz, 2H),
6.93–6.80 (m, 2H), 6.75 (d, J=8.2 Hz, 1H), 5.55 (s, 2H),
5.11 (s, 2H), 3.85 (s, 3H), 3.78 (s, 3H), 2.29 (s, 3H). 13C
NMR (100 MHz, DMSO-d6) δ 197.80, 188.34, 158.51,
151.84, 151.41, 148.71, 148.62, 147.71, 145.25, 143.10,
142.17, 139.39, 138.02, 135.59, 133.42, 130.43, 129.77,
128.49, 125.96, 125.08, 124.75, 124.45, 123.07, 118.28,
116.87, 116.75, 116.32, 116.22, 112.63, 111.95, 61.58,
56.26, 56.06, 53.15, 21.15. ESI-HRMS (m/z): 680.2378
(M+Na), Anal. Calc. for C39H35N3O7Na: 680.2367. Error:
1.6 ppm.
(1E, 6E)-4-(3-((1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)
methoxy)benzylidene)-1,7-bis(4-hydroxy-3-methoxyphenyl)
hepta-1,6-diene-3,5-dione 7 l (C38H32FN3O7), yellow pow-
(1E, 6E)-4-(3-((1-(4-Bromophenyl)-1H-1,2,3-triazol-
4-yl)methoxy)benzylidene)-1,7-bis(4-hydroxy-3-methoxy-
phenyl)hepta-1,6-diene-3,5-dione dione 7o (C37H30BrN3O7),
brick red powder, m. p.: 106–108 °C., 1H NMR (400 MHz,
DMSO-d6) δ 8.97 (s, 1H), 8.00 (s, 1H), 7.93–7.87 (m,
12H), 7.86–7.79 (m, 2H), 7.62 (d, J=15.3 Hz, 1H), 7.50 (d,
J=15.4 Hz, 1H), 7.43–7.34 (m, 3H), 7.27 (m,3H), 7.21–7.12
(m, 2H), 7.07 (dd, J=8.3, 1.8 Hz, 1H), 6.87 (d, J=16.2 Hz,
1H), 6.84 (d, J=8.2 Hz, 1H), 6.73 (d, J=8.2 Hz, 1H), 5.23
(s, 2H), 3.85 (s, 3H), 3.78 (s, 3H). 13C NMR (100 MHz,
DMSO-d6) δ 197.82, 188.36, 158.46, 151.74, 151.29,
148.69, 148.60, 147.75, 145.27, 144.19, 142.21, 139.42,
136.19, 135.65, 133.25, 130.50, 126.06, 125.22, 124.72,
124.43, 123.40, 123.32, 122.54, 121.94, 118.36, 116.76,
116.32, 116.23, 112.64, 111.98, 61.50, 56.26, 56.07.
ESI-HRMS (m/z): 730.1178 (M + Na), Anal. Calc. for
C37H30BrN3O7Na: 730.1159. Error: 2.6 ppm.
1
der, m. p.: 128–130 °C decompose. H NMR (400 MHz,
DMSO-d6) δ 8.29 (s, 1H), 8.02 (s, 1H), 7.62 (d, J=15.4 Hz,
1H), 7.55 (d, J = 15.5 Hz, 1H), 7.45 (d, J = 1.8 Hz, 1H),
7.43–7.38 (m, 3H), 7.38–7.28 (m, 3H), 7.26–7.19 (m, 3H),
7.16 (d, J = 8.0 Hz, 1H), 7.10 (dd, J = 8.3, 1.9 Hz, 2H),
6.91 (d, J=16.2 Hz, 1H), 6.87 (d, J=8.2 Hz, 1H), 6.78 (d,
J=8.2 Hz, 1H), 5.67 (s, 2H), 5.12 (s,2H), 3.86 (s, 3H), 3.79
(s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 197.93, 188.51,
163.61, 161.18, 158.51, 150.67, 150.41, 148.50, 148.44,
147.58, 145.13, 143.18, 142.05, 139.69, 135.54, 132.68,
132.65, 130.84, 130.75, 130.46, 126.56, 125.86, 125.16,
124.89, 124.47, 124.24, 123.12, 118.69, 116.86, 116.19,
116.10, 115.98, 112.68, 112.07, 61.58, 56.32, 56.12, 52.55.
ESI-HRMS (m/z): 684.2130 (M + Na), Anal. Calc. for
C38H32FN3O7Na: 684.2116. Error: 1.9 ppm.
(1E, 6E)-4-(3-((1-(4-Bromophenyl)-1H-1,2,3-triazol-
4-yl)methoxy)benzylidene)-1,7-bis(4-hydroxy-3-methoxy-
phenyl)hepta-1,6-diene-3,5-dione 7m (C38H32BrN3O7),
brick red powder, m. p.: 98–100 °C. 1H NMR (400 MHz,
DMSO-d6) δ 8.29 (s, 1H), 7.97 (s, 1H), 7.65–7.56 (m, 3H),
7.48 (d, J=15.4 Hz, 1H), 7.40 (d, J=1.8 Hz, 1H), 7.38 (d,
J=8.6 Hz, 1H), 7.33 (d, J=8.3 Hz, 1H), 7.32–7.24 (m, 4H),
7.24–7.18 (m, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.12–7.05 (m,
1H), 6.86 (d, J = 16.1 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H),
6.73 (d, J = 8.2 Hz, 1H), 5.60 (s, 2H), 5.12 (s, 2H), 3.85
(s, 3H), 3.78 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ
197.77, 188.29, 158.50, 152.12, 151.61, 148.77, 148.66,
147.76, 145.28, 143.21, 142.22, 139.30, 135.82, 135.61,
132.18, 130.69, 130.44, 125.85, 125.30, 124.97, 124.84,
124.50, 124.25, 123.11, 121.96, 118.20, 116.85, 116.73,
116.35, 116.26, 112.62, 111.92, 61.58, 56.26, 56.06, 52.59.
ESI-HRMS (m/z): 744.1328 (M + Na), Anal. Calc. for
C38H32BrN3O7Na: 744.1316. Error: 1.7 ppm.
(1E, 6E)-4-(3-((1-(3,4-Dichlorophenyl)-1H-1,2,3-triazol-
4-yl)methoxy)benzylidene)-1,7-bis(4-hydroxy-3-methoxy-
phenyl)hepta-1,6-diene-3,5-dione 7p (C37H29Cl2N3O7),
brick red powder, m. p.: 139–141 °C. 1H NMR (400 MHz,
DMSO-d6) δ 9.04 (s, 1H), 8.29 (d, J=2.5 Hz, 1H), 8.04–7.95
(m, 2H), 7.90 (d, J=8.8 Hz, 1H), 7.62 (d, J=15.3 Hz, 1H),
7.50 (d, J = 15.4 Hz, 1H), 7.44–7.34 (m, 3H), 7.30–7.22
(m, 3H), 7.21–7.13 (m, 2H), 7.07 (dd, J=8.3, 1.7 Hz, 1H),
6.91–6.79 (m, 3H), 6.73 (d, J=8.2 Hz, 1H), 5.24 (s, 2H),
3.85 (s, 3H), 3.78 (s, 3H). 13C NMR (100 MHz, DMSO-d6)
δ 197.78, 188.31, 158.44, 151.84, 151.37, 148.70, 148.61,
147.75, 145.27, 144.32, 142.23, 139.35, 136.49, 135.66,
132.85, 132.22, 131.60, 130.50, 125.98, 125.13, 124.73,
124.43, 124.36, 123.60, 123.32, 122.32, 120.60, 118.30,
116.77, 116.32, 116.22, 112.63, 111.95, 61.50, 56.26,
56.06. ESI-HRMS (m/z): 720.1297 (M +Na), Anal. Calc.
for C37H29Cl2N3O7Na: 720.1275. Error: 3.1 ppm.
1 3

Journal of the Iranian Chemical Society
(1E, 6E)-4-(3-((1-Phenyl-1H-1,2,3-triazol-4-yl)meth-
oxy)benzylidene)-1,7-bis(4-hydroxy-3-methoxyphenyl)
hepta-1,6-diene-3,5-dione 7q (C37H31N3O7), brick red
powder, m. p.: 119–121°C.1H NMR (400 MHz, DMSO-
d6) δ 8.95 (s, 1H), 8.01 (s, 1H), 7.95–7.89 (m, 2H), 7.64
(d, J=2.0 Hz, 1H), 7.63–7.59 (m, 2H), 7.54–7.48 (m, 2H),
7.42 (d, J=1.8 Hz, 1H), 7.41–7.34 (m, 2H), 7.30–7.25 (m,
3H), 7.21–7.13 (m, 2H),, 7.07 (dd, J = 8.3, 1.8 Hz, 1H),
6.87 (d, J=16.1 Hz, 1H), 6.83 (d, J=8.2 Hz, 1H), 6.73 (d,
J = 8.2 Hz, 1H), 5.23 (s, 2H), 3.85 (s, 3H), 3.78 (s, 3H).
13C NMR (100 MHz, DMSO-d6) δ 197.83, 188.38, 158.49,
151.80, 151.34, 148.71, 148.62, 147.76, 145.27, 144.00,
142.22, 139.42, 137.02, 135.65, 130.51, 130.37, 129.25,
126.03, 125.20, 124.74, 124.45, 123.39, 123.29, 120.65,
118.35, 116.82, 116.77, 116.33, 116.24, 112.64, 111.98,
61.53, 56.27, 56.07. ESI-HRMS (m/z): 652.2067 (M+Na),
Anal. Calc. for C37H31N3O7Na: 652.2054. Error: 2.0 ppm.
(1E, 6E)-4-(3-((1-(4-Nitrophenyl)-1H-1,2,3-triazol-4-yl)
methoxy)benzylidene)-1,7-bis(4-hydroxy-3-methoxyphenyl)
hepta-1,6-diene-3,5-dione 7r (C37H30N4O9), yellow pow-
hepta-1,6-diene-3,5-dione 7 s (C38H32FN3O7), brick red
powder, m. p.: 106–108 °C. 1H NMR (400 MHz, DMSO-
d6) δ 8.32 (s, 1H), 8.03 (s, 1H), 7.60 (d, J=15.4 Hz, 1H),
7.40–7.32 (m,5H), 7.32–7.25 (m, 3H), 7.23–7.19 (m,
2H), 7.19–7.13 (m, 2H), 7.02 (dd, J = 8.3, 1.8 Hz, 1H),
6.94 (t, J = 7.7 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 6.78 (d,
J=16.1 Hz, 1H), 6.73 (d, J=8.2 Hz, 1H), 5.58 (s, 2H), 5.29
(s, 2H), 3.82 (s, 3H), 3.76 (s,3H). 13C NMR (100 MHz,
DMSO-d6) δ 197.35, 188.35, 163.56, 161.13, 156.93,
151.65, 151.37, 148.68, 148.64, 147.36, 145.41, 143.35,
141.82, 135.12, 132.62, 132.59, 132.15, 130.68, 130.59,
129.87, 125.88, 125.26, 125.21, 124.63, 124.45, 124.29,
123.76, 121.55, 118.88, 116.37, 116.21, 116.15, 115.93,
113.99, 112.42, 111.85, 62.56, 56.18, 56.06, 52.56. HRMS
(m/z): 681.2138 (M+Na), Anal. Calc. for C38H32FN3O7Na:
681.2116. Error: 3.2 ppm.
(1E, 6E)-4-(2-((1-(4-Bromobenzyl)-1H-1,2,3-triazol-
4-yl)methoxy)benzylidene)-1,7-bis(4-hydroxy-3-meth-
oxyphenyl)hepta-1,6-diene-3,5-dione 7t (C38H32BrN3O7),
brick red powder, m. p.: 135–137 °C decompose. 1H NMR
(400 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.01 (s, 1H), 7.60 (d,
J = 15.3 Hz, 1H), 7.55–7.51 (m, 2H), 7.39–7.34 (m, 1H),
7.33–7.26 (m, 4H), 7.24–7.14 (m, 5H), 7.00 (dd, J = 8.3,
1.8 Hz, 1H), 6.93 (t, J = 7.5 Hz, 1H), 6.78 (d, J= 8.2 Hz,
1H), 6.74 (d, J=16.1 Hz, 1H), 6.68 (d, J=8.2 Hz, 1H), 5.58
(s, 2H), 5.29 (s, 2H), 3.80 (s, 3H), 3.75 (s, 3H). 13C NMR
(100 MHz, DMSO-d6) δ 197.27, 188.12, 156.93, 153.08,
152.66, 148.94, 148.86, 147.59, 145.56, 143.38, 141.94,
135.76, 134.69, 132.13, 130.52, 129.84, 125.38, 125.12,
125.02, 124.60, 124.39, 123.81, 121.92, 121.53, 118.34,
116.54, 116.38, 113.96, 112.29, 111.68, 62.53, 56.12, 56.00,
52.60. ESI-HRMS (m/z): 744.1344 (M+Na), Anal. Calc. for
C38H32BrN3O7Na: 744.1316. Error: 2.5 ppm.
1
der, m. p.: 146–148 °C decompose. H NMR (400 MHz,
DMSO-d6) δ 9.15 (s, 1H), 8.48 (d, J = 9.1 Hz,2H), 8.24
(d, J=9.1 Hz, 2H), 8.03 (s, 1H), 7.62 (d, J=15.4 Hz, 1H),
7.55 (d, J = 15.4 Hz, 1H), 7.47–7.35 (m,3H), 7.33–7.21
(m, 3H), 7.20–7.13 (m, 2H), 7.09 (dd, J=8.2, 1.3 Hz, 1H),
6.92–6.84 (m,2H), 6.76 (d, J = 8.2 Hz, 1H), 5.27 (s, 2H),
3.86 (s, 3H), 3.79 (s, 3H). 13C NMR (100 MHz, DMSO-d6)
δ 197.87, 188.46, 158.43, 150.47, 150.26, 148.39, 147.55,
147.23, 145.09, 144.68, 142.09, 141.22, 139.63, 135.61,
130.55, 126.60, 126.01, 125.92, 124.91, 124.40, 124.16,
123.78, 123.38, 121.16, 118.71, 116.86, 116.75, 116.15,
116.02, 112.72, 112.08, 61.46, 56.30, 56.11. ESI-HRMS
(m/z): 697.1914 (M+Na), Anal. Calc. for C37H30N4O9Na:
697.1905. Error: 1.3 ppm.
(1E, 6E)-4-(2-((1-(4-Methylbenzyl)-1H-1,2,3-triazol-
4-yl)methoxy)benzylidene)-1,7-bis(4-hydroxy-3-meth-
oxyphenyl)hepta-1,6-diene-3,5-dione 7u (C39H35N3O7),
brick red powder, m. p.: 111–113 °C. 1H NMR (400 MHz,
DMSO-d6) δ 8.28 (s, 1H), 8.04 (s, 1H), 7.60 (d, J=15.4 Hz,
1H), 7.40–7.35 (m, 2H), 7.34–7.26 (m, 3H), 7.26–7.20 (m,
3H), 7.18–7.10 (m, 4H), 7.02 (dd, J = 8.3, 1.9 Hz, 1H),
6.93 (t, J = 7.4 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 6.77 (d,
J=16.1 Hz, 1H), 6.73 (d, J=8.2 Hz, 1H), 5.52 (s, 2H), 5.28
(s, 2H), 3.82 (s, 3H), 3.76 (s, 3H), 2.25 (s, 3H). 13C NMR
(100 MHz, DMSO-d6) δ 197.30, 188.30, 156.93, 151.90,
151.60, 148.72, 148.67, 147.36, 145.41, 143.28, 141.87,
137.97, 135.03, 133.35, 132.11, 129.85, 129.74, 128.32,
125.74, 125.11, 124.68, 124.37, 123.76, 121.51, 118.72,
116.38, 116.22, 113.93, 112.39, 111.82, 62.56, 56.17, 56.05,
53.15, 21.12. ESI-HRMS (m/z): 680.2382 (M+Na), Anal.
Calc. for C39H35N3O7Na: 680.2367. Error: 2.1 ppm.
(1E, 6E)-4-(2-(Prop-2-ynyloxy)benzylidene)-1,7-bis(4-
hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione 5c
(C31H26O7), brick red powder, m. p.: 118–120 °C. 1H NMR
(400 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.63 (d, J=15.4 Hz,
1H), 7.41–7.36 (m, 2H), 7.35–7.26 (m, 3H), 7.24–7.20 (m,
2H), 7.16 (d, J=8.0 Hz, 1H), 7.03 (dd, J=8.3, 1.8 Hz, 1H),
6.96 (m, 1H), 6.82 (d, J=8.2 Hz, 1H), 6.78 (d, J=16.1 Hz,
1H), 6.74 (d, J=8.2 Hz, 1H), 4.96 (d, J=2.3 Hz, 1H), 3.83
(s, 3H), 3.78 (s, 3H), 3.65 (t, J = 2.3 Hz, 1H). 13C NMR
(100 MHz, DMSO-d6) δ 197.20, 188.31, 155.95, 151.69,
151.42, 148.68, 148.63, 147.36, 145.51, 142.13, 135.00,
131.94, 129.93, 125.83, 125.20, 124.68, 124.43, 123.71,
121.69, 118.94, 116.33, 116.21, 113.48, 112.40, 111.78,
79.47, 79.21, 56.57, 56.19, 56.07. ESI-HRMS (m/z):
533.1588 (M+Na), Anal. Calc. for C31H26O7Na: 533.1571.
Error: 3.2 ppm.
(1E, 6E)-4-(2-((1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)
methoxy)benzylidene)-1,7-bis(4-hydroxy-3-methoxyphenyl)
( 1 E ,
6 E ) - 4 - ( 2 - ( ( 1 - ( 4 - B r o m o p h e n y l ) -
1 H - 1 , 2 , 3 - t r i a z o l - 4 - y l ) m e t h o x y )
1 3

Journal of the Iranian Chemical Society
benzylidene)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-
1,6-diene-3,5-dione 7v (C37H30BrN3O7), brick red powder,
m. p.: 119–121 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.01
(s, 1H), 8.10 (s, 1H), 7.87–7.81 (m, 2H), 7.80–7.73 (m, 2H),
7.59 (d, J=15.4 Hz, 1H), 7.43–7.38 (m, 1H), 7.37–7.23 (m,
5H), 7.22–7.17 (m, 2H), 7.01 (dd, J=8.3, 1.8 Hz, 1H), 6.96
(t, J=7.9 Hz, 1H), 6.81–6.74 (m, 2H), 6.70 (d, J=8.2 Hz,
1H), 5.40 (s, 2H), 3.80 (s, 3H), 3.76 (s, 3H). 13C NMR
(100 MHz, DMSO-d6) δ 197.27, 188.38, 156.85, 151.70,
151.36, 148.68, 148.58, 147.35, 145.44, 144.41, 141.89,
136.10, 135.07, 133.22, 132.20, 129.92, 125.81, 125.21,
124.66, 124.41, 124.26, 123.77, 123.36, 122.39, 121.94,
121.64, 118.84, 116.31, 116.20, 113.88, 112.39, 111.80,
62.42, 56.14, 56.06. ESI-HRMS (m/z): 730.1185 (M+Na),
Anal. Calc. for C37H30BrN3O7Na: 730.1159. Error: 3.5 ppm.
(1E, 6E)-4-(2-((1-(3,4-Dichlorophenyl)-1H-1,2,3-triazol-
4-yl)methoxy)benzylidene)-1,7-bis(4-hydroxy-3-methoxy-
phenyl)hepta-1,6-diene-3,5-dione7w (C37H29Cl2N3O7),
brick red powder, m. p.: 108–111 °C. 1H NMR (400 MHz,
DMSO-d6) δ 9.08 (s, 1H), 8.23 (d, J = 2.5 Hz, 1H), 8.08
(s, 1H), 7.91 (dd, J=8.8, 2.5 Hz, 1H), 7.83 (d, J=8.8 Hz,
1H), 7.58 (d, J=15.4 Hz, 1H), 7.44–7.38 (m, 1H), 7.37–7.27
(m, 4H), 7.26–7.20 (m,2H), 7.17 (dd, J=8.3, 1.8 Hz, 1H),
7.01 (dd, J = 8.3, 1.8 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H),
6.80–6.75 (m, 2H), 6.71 (d, J=8.2 Hz, 1H), 5.40 (s, 2H),
3.79 (s, 3H), 3.77 (s, 3H).13C NMR (100 MHz, DMSO-d6)
δ 197.21, 188.39, 156.84, 151.56, 151.22, 148.64, 148.52,
147.31, 145.42, 144.47, 141.88, 136.38, 135.06, 132.85,
132.17, 131.61, 129.93, 125.84, 125.28, 124.62, 124.44,
124.16, 123.79, 123.61, 122.18, 121.68, 120.42, 118.94,
116.25, 116.16, 113.93, 112.34, 111.78, 62.40, 56.10,
56.05.. ESI-HRMS (m/z): 720.1309 (M+Na), Anal. Calc.
for C37H29Cl2N3O7Na: 720.1275. Error: 4.8 ppm.
9.18 (s, 1H), 8.44–8.37 (m, 2H), 8.20–8.14 (m, 2H), 8.10 (s,
1H), 7.58 (d, J=15.4 Hz, 1H), 7.44–7.39 (m, 1H), 7.38–7.28
(m, 4H), 7.28–7.19 (m, 2H), 7.16 (dd, J=8.3, 1.8 Hz, 1H),
7.03–6.94 (m, 2H), 6.80–6.71 (m, 2H), 6.69 (d, J=8.2 Hz,
1H), 5.43 (s, 2H), 3.78 (s, 3H), 3.76 (s, 3H). 13C NMR
(100 MHz, DMSO-d6) δ 197.17, 188.50, 162.80, 156.80,
151.77, 151.35, 148.67, 148.54, 147.32, 147.13, 145.40,
144.86, 141.91, 141.08, 135.03, 132.21, 129.93, 125.93,
125.75, 125.12, 124.67, 124.33, 124.18, 123.76, 123.74,
121.71, 120.94, 118.84, 116.24, 116.18, 113.89, 112.27,
111.70, 62.38, 56.08, 56.02. ESI-HRMS (m/z): 697.1925
(M+Na), Anal. Calc. for C37H30N4O9Na: 697.1905. Error:
3.2 ppm.
Determination of MICs
Broth micro-dilution method was carried out according to
the standard protocols recommended by Clinical Labora-
tory Standard Institute (CLSI) [43] to determine the mini-
mum concentration of each antimicrobial agent required
for inhibition (MIC) of visible growth of tested bacterium
and fungal. In brief, twofold serial dilutions of each com-
pound were made in a concentration range from 0.125 to
256 µg/ml in sterile plastic micro-dilution trays containing
Mueller-Hinton broth (MHB). Thereafter, bacterial suspen-
sion of each bacterial strain was prepared from freshly cul-
tured bacteria in sterile normal saline that were adjusted
to 0.5 McFarland standard turbidity. The suspension was
further diluted (1:100) by sterile MHB just before adding
to the trays containing a serial dilution of each compound.
MICs were recorded after 22 h incubation at 37 °C. Cefixime
was used as standard antibiotic and all experiments were
done in triplicate.
(1E, 6E)-4-(2-((1-Phenyl-1H-1,2,3-triazol-4-yl)methoxy)
benzylidene)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-
1,6-diene-3,5-dione 7x (C37H31N3O7), brick red powder, m.
QSAR
1
p.: 99–101 °C. H NMR (400 MHz, DMSO-d6) δ 8.99 (s,
1H), 8.11 (s, 1H), 7.88–7.84 (m, 2H), 7.64–7.46 (m, 4H),
7.43–7.15 (m, 8H), 7.01 (dd, J = 8.3, 1.8 Hz, 1H),6.96 (t,
J=7.3 Hz, 1H), 6.80–6.75 (m, 2H), 6.70 (d, J=8.2 Hz, 1H),
5.41 (s, 2H), 3.80 (s, 3H), 3.76 (s, 3H). 13C NMR (100 MHz,
DMSO-d6) δ 197.31, 188.33, 156.87, 151.84, 151.49,
148.71, 148.61, 147.37, 145.46, 144.25, 141.90, 136.93,
135.00, 132.19, 130.36, 129.91, 129.27, 128.12, 125.73,
125.11, 124.71, 124.29, 123.75, 123.33, 121.60, 120.62,
120.52, 118.72, 116.34, 116.21, 114.61, 113.85, 112.38,
111.76, 60.65, 56.12, 56.04. ESI-HRMS (m/z): 652.2085
(M+Na), Anal. Calc. for C37H31N3O7Na: 652.2054. Error:
4.8 ppm.
In this study, quantitative structure activity relationship
(QSAR) modeling was performed to determine the structural
descriptors which correlate to the antibacterial and antifun-
gal activities with the synthesized curcumin derivatives. The
training set contained 23 compounds was used for model
generation, and the remaining five molecules were used as
test set to evaluate the prediction ability of generated QSAR
model.
Molecular structures of all compounds were generated
using the Hyperchem software (Ver. 7.0) [44].
3D structures were optimized based on semi empirical
AM1 method using the Polak-Ribiere Powell conjugated
gradient algorithm method with convergence criterion of
0.01 kcal/mol.
(1E, 6E)-4-(2-((1-(4-Nitrophenyl)-1H-1,2,3-triazol-4-yl)
methoxy)benzylidene)-1,7-bis(4-hydroxy-3-methoxyphenyl)
hepta-1,6-diene-3,5-dione 7y (C37H30N4O9), brick red pow-
der, m. p.:116–118 °C. 1H NMR (400 MHz, DMSO-d6) δ
Then 1875 molecular descriptors were calculated using
the PaDEL software [45].
1 3

Journal of the Iranian Chemical Society
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reduce non-useful and redundant descriptors.
In the next step, among descriptors encoding similar
information based on correlation coefficients greater than
0.80, the one which had the highest correlation with MIC
values was retained and the other one was removed. Finally,
a stepwise MLR model was used to select the most impor-
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