Synthesis, evaluation, and molecular docking studies of aryl urea-triazole-based derivatives as anti-urease agents

Article abstract of DOI:10.1002/ardp.201800005

Considering the importance of urease inhibitors in the treatment of ureolytic bacterial infections, in this work, the synthesis of novel, aryl urea-triazole-based derivatives as effective urease inhibitors is described. Dichloro-substituted derivative 4o,

Full text of DOI:10.1002/ardp.201800005

Received: 8 January 2018
Revised: 28 April 2018
Accepted: 2 May 2018
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DOI: 10.1002/ardp.201800005
FULL PAPER
Synthesis, evaluation, and molecular docking studies of aryl
urea-triazole-based derivatives as anti-urease agents
Setareh Moghimi1
Fereshteh Goli-Garmroodi2
Maryam Allahyari-Devin3
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Hedieh Pilali2
Malihe Hassanzadeh1
Shabnam Mahernia1
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Mohammad Mahdavi4
Alireza Foroumadi1,5
Loghman Firoozpour2
Massoud Amanlou1,5
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1 The Institute of Pharmaceutical Sciences
(TIPS), Tehran University of Medical Sciences,
Tehran, Iran
Abstract
Considering the importance of urease inhibitors in the treatment of ureolytic
bacterial infections, in this work, the synthesis of novel, aryl urea-triazole-based
derivatives as effective urease inhibitors is described. Dichloro-substituted
derivative 4o, with IC50 = 22.81 0.05 μM, is found to be the most potent urease
inhibitor, determined by Berthelot colorimetric assay. Docking studies were also
carried out for compound 4o to confirm the effective interactions with the urease
active site.
2 Drug Design and Development Research
Center, The Institute of Pharmaceutical
Sciences (TIPS), Tehran University of Medical
Sciences, Tehran, Iran
3 Department of Medicinal Chemistry, School
of Pharmacy, Urmia University of Medical
Science, Urmia, Iran
4 Endocrinology and Metabolism Research
Center, Endocrinology and Metabolism
Research Institute, Tehran University of
Medical Sciences, Tehran, Iran
K E Y W O R D S
5 Department of Medicinal Chemistry, Faculty
of Pharmacy, Tehran University of Medical
Sciences, Tehran, Iran
click reaction, docking study, triazole, urease
Correspondence
Dr. Alireza Foroumadi, Department of
Medicinal Chemistry, Faculty of Pharmacy,
Tehran University of Medical Sciences,
Tehran, Iran.
Email: aforoumadi@yahoo.com
Funding information
The Institute of Pharmaceutical Sciences
(TIPS), Tehran University of Medical Sciences
(TUMS), Grant number: 97-01-45-37514
disease of humans.[11] For instance, the best condition for colonization
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1
INTRODUCTION
and survival of Helicobacter pylori (H. pylori) in acidic medium of the
Urease (EC 3.5.1.5) is a large dinuclear metalloenzyme from the
amidohydrolase family,[1–3] which is known as the first purified enzyme
molecule in its crystalline form.[4] This enzyme, depending on its sources
(soil,[5] bacteria, fungi,[6–9] and plants[10]), plays critical roles in plant
growth, agriculture, human and animal health. Bacterial urease has been
contributed as the prominent antigenic component in some infectious
stomach is provided by virtue of the ureolytic activity. The alkaline
character of produced ammonia, which normally leads to elevated pH
values generates the required environment for H. pylori survival.[12–14] In
this regard, depending on colonization site, various types of diseases
including peptic, duodenal, gastric ulcer, and urinary tract infection[15–17]
have occurred, which affected approximately 3 billion people around the
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Arch Pharm Chem Life Sci. 2018;e1800005.
wileyonlinelibrary.com/journal/ardp
© 2018 Deutsche Pharmazeutische Gesellschaft
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https://doi.org/10.1002/ardp.201800005

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MOGHIMI ET AL.
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world. These H. pylori-associated diseases prevalently occur in develop-
ing countries and increase the risk of third leading cause of death
worldwide, meaning gastric cancer.
ascorbate to generate 1-((1-substituted benzyl)-1H-1,2,3-triazol-4-yl)
methyl)-3-phenyl urea derivatives. Regarding the critical role of copper
catalyst inthistransformation, itwas foundthat 0.1 molofcoppersulfate
in 10 mL of H2O/t-BuOH yielded the desired products in good yields.
The generality of this protocol was subsequently examined, by
employing a variety of benzyl halides. Electron-donating and electron
withdrawing groups at different positions of phenyl ring underwent
click reaction to furnish the desired products in good yields. Seventeen
representative examples of this class were synthesized and confirmed
by IR, 1H and 13C NMR spectroscopy.
To reduce the risk of this disease, the development of urease
inhibitors[18,19] triggers enticing attention of several research groups to
introduce more efficient agents. The urease inhibitory activity has
been observed in compounds with different structural motifs,
including heavy metal complexes[20] and various organic scaf-
folds.[21–31] Meanwhile, the promising importance of aryl urea class
of inhibitors has driven extensive efforts to consider homologues of
this moiety as a leading pattern in designing novel inhibitors. This
activity can be related to the capability of urea moiety in filling the
distance between the catalytic site and the surrounding residue.
1,2,3-Triazole is one of the most potent nuclei in bioactive
compounds,[32] widely studied for the beneficial biological effects.
Apart from this medicinal value, a literature survey[33–36] reveals the
substantial applicability of triazole containing molecules in drug
delivery agents, tissue engineering, and organometallic ligands which
will be served in light emitting devices, solar energy conversion and as a
organocatalyst in organic transformations.
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2.2 Biological evaluation
The profile of antiurease activity of 4a–q was established by Berthelot
colorimetric method. The influence of different substituents at benzyl
and phenyl ring on urease inhibitory activity can be observed in Table 1.
The results revealed that good urease inhibitory activity is dependent
upon the presence of methoxy at para position of phenyl ring. As
summarized in Table 1, the presence of methoxy group has a positive
effect on inhibitory activity (IC50s ranged from 22 to 96 μM) compared
to unsubstituted counterparts. The unsubstituted derivatives are three-
to fivefold less potent than p-methoxy-substituted derivatives.
The observations suggested that the presence of substituents
(fluoro and chloro) at the para position of the benzyl ring results in
promising inhibitory activities. While moving these substituents to the
ortho and meta positions leads to the reduced activities. The p-
substituted fluorine group improves the antiurease activity compared
to chloro and bromo bearing derivatives in both series. These
observations suggested that more electron-withdrawing group could
enhance the inhibitory activity. The presence of a large and lipophilic
group at para position, meaning bromine, causes increased IC50 value.
Dichloro-substituted derivatives are the most potent compounds in
both series. Maintaining the p-chloro group, introduction of a second
chloro group in ortho and meta positions led to the increased inhibitory
potencies. It seems that the presence of two chlorine atoms provides
appropriate spatial arrangement to fit in active site and subsequently
enhanced the inhibitory activity against urease.
Traditionally, the main approach for the construction of 1,
4-disubstituted triazoles is the copper-catalyzed azide-alkyne cycload-
dition reaction (CuAAC).[37] This reaction provides an experimentally
simple and mild pathway for the formation of carbon-heteroatom bond,
affording triazoles in a single step procedure. In terms of unique
propertiesassociatedwiththistypeof reaction,manytriazole-containing
molecules have been prepared through the simple and efficient click
reaction.[38–40] Taking this into account and the importance of urea and
triazole[41,42] moieties in urease inhibitors, we now report the synthesis
and antiurease activity of novel 1-((1-substituted benzyl)-1H-1,2,
3-triazol-4-yl)methyl)-3-phenyl urea derivatives.
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2
RESULTS AND DISCUSSION
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2.1 Chemistry
Treatment of phenyl isocyanate and 4-methoxy phenyl isocyanate with
propargyl amine 2 in dichloromethane gave the propargylated product 3
(Scheme 1). The reaction was carried out according to the previously
reported procedure.[43,44] Then, 1-(substituted phenyl)-3-(prop-2-ynyl)
urea 3 undergo click reaction with commercially available benzyl halides
(chloride and bromide), sodium azide, copper sulfate, and sodium
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2.3 Docking studies
The binding mode of compound 4o illustrated that the NH and
methoxy groups formed hydrogen bonds with Asp494 and Arg439,
SCHEME 1 Synthsis of compounds 4. Reagents and conditions: (a) CH2Cl2, 20°C; (b) (i) ArCH2Br(Cl), NaN3, H2O/t-BuOH (1:1), Et3N; (ii) 3,
CuSO4, sodium ascorbate, r.t.

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TABLE 1 Urease inhibitory activity of compounds 4a–q
Entry
1
Compound
R1
R2
IC50 (μM)a SEM
149.85 0.12
173.01 1.33
140.91 0.29
169.15 2.02
192.17 1.20
161.21 1.52
184.43 2.16
127.68 1.8
118.73 0.22
46.23 0.08
54.26 0.56
39.11 1.06
73.02 0.21
51.12 1.14
22.81 0.05
37.4 1.20
Docking energy (kcal/mol)
4a
H
2-F
−6.4
−5.7
−6.4
−6.1
−5.4
−6.2
−5.5
−6.4
−6.5
−7.3
−6.9
−7.7
−6.7
−6.9
−7.9
−7.7
−6.8
2
4b
H
3-F
3
4c
H
4-F
4
4d
H
2-Cl
3-Cl
4-Cl
4-Br
2,4-diCl
3,4-diCl
2-F
5
4e
H
6
4f
H
7
4g
H
8
4h
H
9
4i
H
10
11
12
13
14
15
16
17
18
19
4j
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
–
4k
3-F
4l
4-F
4m
3-Cl
4-Cl
2,4-diCl
3,4-diCl
4-Me
–
4n
4o
4p
4q
96.16 0.37
100 0.15
Hydroxyurea
Thiourea
–
–
23 1.7
aValues were the means of three replicates standard deviation (SD).
respectively (Figure 1). The triazole ring exhibited hydrogen bonding
interaction with CME 592. The notable π–alkyl interactions are
observed with His409, His492, His593, His519, Met637, Ala636,
Ala440, and Ala436. The appropriate interaction with nickel could
be observed in the active site. In addition, the Van der Waals
interaction is observed for 4o with His594, CME-592, Arg609,
Asp633, KCX490, and Gly550 for compound 4o.
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2.4 Molecular properties prediction
The ADME properties of the synthesized compounds were evaluated by
Molinspiration online toolkit and the Lipinski's molecular properties are
shown in Table 2. This in silico study under Lipinski's “Rule of five”
determined the drug-likeness of compounds in comparison to known
drugs.[45] Good oral bioavailability of tested compounds depended on the
<5 values of logP, MW (<500), HBA (≤10), and HBD (<5). The molecular
flexibility isdeterminedbythenumberofrotatablebonds(nROTB)values
which should be <10. Furthermore, the topological polar surface area
(TPSA) range of synthesized compounds indicated the good permeability
of the evaluated compounds in the cellular plasma membrane. Finally,
according to ADME findings, no violations were found for the
synthesized compounds, affording positive drug-likeness values.
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3
CONCLUSION
In this paper, the synthesis and in vitro urease inhibition of 17 aryl
urea-triazole-based compounds are presented. All prepared
FIGURE 1 Docking pose of 4o

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MOGHIMI ET AL.
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TABLE 2 In silico molecular properties calculations of compounds 4a–qa,b
Compound
miLog P
2.71
2.73
2.76
3.22
3.25
3.27
3.40
3.88
3.88
2.77
2.79
2.81
3.30
3.33
3.93
3.93
3.10
MW
nON
6
nOHNH
Violations
nROTB
TPSA
71.84
71.84
71.84
71.84
71.84
71.84
71.84
71.84
71.84
81.08
81.08
81.08
81.08
81.08
81.08
81.08
81.08
Volume
286.24
286.24
286.24
294.84
294.84
294.84
299.19
308.38
308.38
311.78
311.78
311.78
320.39
320.39
333.92
333.92
323.41
4a
4b
4c
4d
4e
4f
325.35
325.35
325.35
341.80
341.80
341.80
386.25
376.25
376.25
355.37
355.37
355.37
371.83
371.83
406.27
406.27
351.41
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
6
6
6
6
6
6
6
4g
4h
4i
6
6
6
4j
7
4k
4l
7
7
4m
4n
4o
4p
4q
7
7
7
7
7
aLogP, octanol/water partition coefficient; TPSA, topological polar surface area; MW, molecular weight; nON, number of hydrogen bond acceptors; nOHNH,
number of hydrogen bond donors; nrotb, number of rotatable bonds.
bData were obtained from http://www.molinspiration.com/cgi-bin/properties (accessed 04.23.18).
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derivatives are characterized by spectral data. Among the
synthesized compounds, 4-methoxy bearing derivatives are more
potent urease inhibitors with acceptable ADME properties. It is
concluded that dichloro-substituted derivatives are attractive
candidates for further development to discover novel urease
inhibitors.
4.1.2 General procedure for the synthesis of
compounds 4a–q
The corresponding benzyl halide (1 mmol), sodium azide (1 mmol), and
triethyl amine (1 mmol) were stirred at room temperature in (H2O/t-
BuOH 1:1) (5 mL) for 2 h. Afterward, a solution of compound 3
(1 mmol), CuSO4 (10 mol%) and sodium ascorbate (10–15 mol%) in
(H2O/t-BuOH 1:1) (5 mL) and stirred for 24 h. The crude mixture was
purified by column chromatography (petroleum ether/ethyl acetate
4:1) to afford the desired compounds.
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4
EXPERIMENTAL
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4.1 Chemistry
1-((1-(2-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-3-
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4.1.1 General
phenylurea (4a)
Yellow solid; yield: 72%; mp: 232–234°C; IR (KBr): 3180, 1654
Melting points were determined with a Kofler hot stage apparatus
and are uncorrected. 1H and 13C NMR spectra were recorded
−1
;
1H NMR (500 MHz, DMSO-d6): 4.32 (d, J = 5.5 Hz,

(C O) cm
CH2NH), 5.63 (s, CH2N), 6.55–6.57 (m, 1H triazole), 6.89 (t, J = 7.0 Hz,
with
a
Bruker FT-500, using TMS as an internal standard.
Nicolet Magna FTIR 550
IR spectra were recorded on
a
spectrophotometer using KBr disks. Mass spectra were
obtained with an Agilent Technology (HP) mass spectrometer
operating at an ionization potential of 70 eV. Elemental analysis
for C, H, and N was determined with an Elementar Analysen
System GmbH VarioEL CHNS mode. Figure 2 shows the atom
numbering of compounds 5a,e,o, only used for NMR spectra
interpretation.
The NMR spectra and the InChI codes of the investigated
compounds together with some biological activity data are provided as
Supporting Information.
FIGURE 2 Atom numbering of compounds 4a–q only used for
NMR spectra interpretation

MOGHIMI ET AL.
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H4), 7.20–7.22 (m, H3,5,2′,5′,6′), 7.37–7.38 (m, H2,6,4′), 7.96 (s, NH), 8.48
(s, NH). 13C NMR (125 MHz, DMSO-d6): 34.7 (CH2NH), 46.7 (CH2N),
115.6 (d, C3′Ar, J = 20 Hz), 117.7 (C2,6Ar), 121.0 (Cb triazole), 122.7
(C4Ar), 123.7, 124.7, 128.5 (C3,5Ar), 130.6 (C1Ar), 133.5, 137.1, 139.2,
140.2 (Ca triazole), 145.7, 155.0 (CO), 161.0 (d, C2′Ar, J = 225 Hz). Anal.
calcd. for C17H16FN5O: C, 62.76; H, 4.96; N, 21.53. Found C, 62.59; H,
5.10; N, 21.68.
(m, H2,6,4′,5′), 8.04 (s, NH), 8.50 (s, NH); 13C NMR (125 MHz, DMSO-
d6): 34.8 (CH2NH), 51.9 (CH2N), 117.7 (C2,6Ar), 121.0 (Cb triazole),
122.7 (C4Ar), 123.8, 126.5, 127.6, 127.8, 128.0, 128.5 (C3,5Ar), 130.5
(C1Ar), 133.2, 138.4, 140.2 (Ca triazole), 145.9, 155.0 (CO). Anal. calcd.
for C17H16ClN5O: C, 59.74; H, 4.72; N, 20.49. Found C, 59.59; H, 4.95;
N, 20.60.
1-((1-(4-Chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-3-
phenylurea (4f)
1-((1-(3-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-3-
phenylurea (4b)
Pale yellow solid; yield: 63%; mp: 142–144°C; IR (KBr): 3139, 1692
(CO) cm−1; 1H NMR (500 MHz, DMSO-d6): 4.32 (d, J = 5.0 Hz, CH2NH),
5.57 (s, CH2N), 6.53–6.55 (m, 1H triazole), 6.89 (t, J = 8.0 Hz, H4), 7.21
(t, J = 7.5 Hz, H3,5), 7.33 (d, J = 7.5 Hz, H2′,6′), 7.37 (d, J = 7.5 Hz, H3′,5′),
7.43 (d, J = 7.5 Hz, H2,6), 8.00 (s, NH), 8.49 (s, NH); 13C NMR (125 MHz,
DMSO-d6): 34.8 (CH2NH), 51.8 (CH2N), 117.7 (C2,6Ar), 121.0 (Cb
triazole), 122.7 (C4Ar), 124.3, 128.5 (C3,5Ar), 129.8, 130.6 (C1Ar),
White solid; yield: 70%; mp: 216–218°C; IR (KBr): 3145, 1679
(C O) cm−1; 1H NMR (500 MHz, DMSO-d6): 4.34 (s, CH2NH), 5.60 (s,

CH2N), 6.55–6.57 (m, 1H triazole), 6.89–6.90 (m, H4), 7.15–7.18 (m,
H
3,5,4′), 7.20–7.23 (m, H2′,6′), 7.37–7.39 (m, H2,6,5′), 8.05 (s, NH), 8.49
(s, NH); 13C NMR (125 MHz, DMSO-d6): 34.8 (CH2NH), 51.9 (CH2N),
114.6 (d, C4′Ar, J = 19 Hz), 117.7 (C2,6Ar), 121.0 (Cb triazole), 122.5
(C4Ar), 123.9, 124.8, 125.6, 127.3, 128.5 (C3,5Ar), 130.6 (C1Ar), 138.6,

132.7, 135.0, 140.2 (Ca triazole), 142.2, 145.8, 155.0 (C O). Anal.

140.2 (Ca triazole), 146.4, 155.0 (C O), 162.4 (d, C3′Ar, J = 205 Hz).
calcd. for C17H16ClN5O: C, 59.74; H, 4.72; N, 20.49. Found C, 59.98; H,
4.59; N, 20.31.
Anal. calcd. for C17H16FN5O: C, 62.76; H, 4.96; N, 21.53. Found C,
62.89; H, 4.80; N, 21.32.
1-((1-(4-Bromobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-3-
1-((1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-3-
phenylurea (4c)
phenylurea (4g)
Pale yellow solid; yield: 74%; mp: 176–178°C; IR (KBr): 3201, 1666
−1
Orange solid; yield: 69%; mp: 189–191°C; IR (KBr): 3180, 1648
(CO) cm−1; 1H NMR (500 MHz, DMSO-d6): 4.32 (d, J = 5.0 Hz, CH2NH),
5.56 (s, CH2N), 6.52–6.54 (m, 1H triazole), 6.89 (t, J = 7.0 Hz, H4), 7.17–
7.22 (m, H3,5,3′,5′), 7.37–7.38 (m, H2,6,2′,6′), 7.99 (s, NH), 8.48 (s, NH);
13C NMR (125 MHz, DMSO-d6): 34.8 (CH2NH), 51.8 (CH2N), 115.3 (d,
1H NMR (500 MHz, DMSO-d6): 4.32 (d, J = 5.0 Hz,

(C O) cm ;
CH2NH), 5.56 (s, CH2N), 6.54–6.57 (m, 1H triazole), 6.89 (t, J = 8.5 Hz,
H4), 7.21 (t, J = 7.5 Hz, H3,5), 7.26 (d, J = 7.5 Hz, H2′,6′), 7.37 (d,
J = 7.5 Hz, H3′,5′), 7.56 (d, J = 8.0 Hz, H2,6), 8.00 (s, NH), 8.48 (s, NH);
13C NMR (125 MHz, DMSO-d6): 34.8 (CH2NH), 51.9 (CH2N), 117.7
(C2,6Ar), 121.0 (Cb triazole), 121.2, 122.6 (C4Ar), 128.5 (C3,5Ar), 130.1
(C1Ar), 131.4, 131.6, 134.2, 135.4, 140.2 (Ca triazole), 145.8, 154.9
(CO). Anal. calcd. for C17H16BrN5O: C, 52.86; H, 4.18; N, 18.13. Found
C, 53.06; H, 4.35; N, 18.02.
C3′,5′Ar, J = 21 Hz), 117.7 (C2,6Ar), 121.0 (Cb triazole), 122.7 (C4Ar),
125.4, 128.5 (C3,5Ar), 130.1 (C1Ar), 132.3, 136.2, 140.2 (Ca triazole),
146.0, 155.0 (CO), 162.0 (d, C4′Ar, J = 220 Hz). Anal. calcd. for
C17H16FN5O: C, 62.76; H, 4.96; N, 21.53. Found C, 62.91; H, 5.14; N,
21.70.
1-((1-(2,4-Dichlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-3-
1-((1-(2-Chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-3-
phenylurea (4h)
phenylurea (4d)
Yellow solid; yield: 70%; mp: 221–222°C; IR (KBr): 3177, 1645
−1
Pale yellow solid; yield: 66%; mp: 180–182°C; IR (KBr): 3200, 1678
1H NMR (500 MHz, DMSO-d6): 4.34 (d, J = 5.0 Hz,

(C O) cm ;
−1
1H NMR (500 MHz, DMSO-d6): 4.34 (d, J = 5.5 Hz,
CH2NH), 5.67 (s, CH2N), 6.54–6.56 (m, 1H triazole), 6.89 (t, J = 7.0 Hz,

(C O) cm
;
CH2NH), 5.68 (s, CH2N), 6.55 (t, J = 5.5 Hz, 1H triazole), 6.89 (t,
H4), 7.21 (t, J = 7.0 Hz, H3,5), 7.26 (d, J = 8.5 Hz, H6′), 7.38 (d, J = 7.5 Hz,
J = 7.0 Hz, H4), 7.20–7.23 (m, H3,5,6′), 7.30–7.33 (m, H4′), 7.36–7.39 (m,
H2,6), 7.45 (d, J = 8.5 Hz, H5′), 7.67 (s, H3′), 7.98 (s, NH), 8.50 (s, NH);
H
2,6,5′), 7.50 (d, J = 7.0 Hz, H3′), 7.97 (s, NH), 8.49 (s, NH); 13C NMR
13C NMR (125 MHz, DMSO-d6): 34.8 (CH2NH), 49.8 (CH2N), 117.7
(C2,6Ar), 121.1 (Cb triazole), 123.0 (C4Ar), 127.7, 128.5 (C3,5Ar), 129.0,
130.8 (C1Ar), 131.1, 133.4, 133.8, 134.0, 140.0 (Ca triazole), 145.7,
(125 MHz, DMSO-d6): 34.7 (CH2NH), 50.4 (CH2N), 117.7 (C2,6Ar),
121.0 (Cb triazole), 123.0 (C4Ar), 127.6, 128.5 (C3,5Ar), 129.4, 129.9,
130.1 (C1Ar), 130.3, 132.5 133.2, 140.2 (Ca triazole), 142.3, 145.6,

147.4, 154.9 (C O). Anal. calcd. for C17H15Cl2N5O: C, 54.27; H, 4.02;

155.0 (C O). Anal. calcd. for C17H16ClN5O: C, 59.74; H, 4.72; N,
N, 18.61. Found C, 54.40; H, 4.20; N, 18.48.
20.49. Found C, 59.91; H, 4.59; N, 20.22.
1-((1-(3,4-Dichlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-3-
1-((1-(3-Chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-3-
phenylurea (4i)
phenylurea (4e)
Pale yellow solid; yield: 71%; mp: 183–185°C; IR (KBr): 3098, 1679
−1
Yellow solid; yield: 81%; mp: 151–153°C; IR (KBr): 3161, 1655
1H NMR (500 MHz, DMSO-d6): 4.32 (d, J = 5.0 Hz,

(C O) cm ;
−1
1H NMR (500 MHz, DMSO-d6): 4.34 (d, J = 5.0 Hz,
CH2NH), 5.59 (s, CH2N), 6.53–6.55 (m, 1H triazole), 6.89 (t, J = 7.0 Hz,

(C O) cm
;
CH2NH), 5.59 (s, CH2N), 6.54–6.56 (m, 1H triazole), 6.89 (t, J = 7.0 Hz,
H4), 7.21 (t, J = 7.5 Hz, H3,5), 7.28 (d, J = 8.0 Hz, H6′), 7.37 (d, J = 7.5 Hz,
H4), 7.21 (t, J = 7.5 Hz, H3,5), 7.24–7.27 (m, 2′,6′), 7.38–7.39
H
H2,6), 7.61 (s, H2′), 7.62 (d, J = 8.0 Hz, H5′), 8.04 (s, NH), 8.49 (s, NH);

6 of 8
MOGHIMI ET AL.
|
13C NMR (125 MHz, DMSO-d6): 34.8 (CH2NH), 51.2 (CH2N), 117.7
(C2,6Ar), 121.0 (Cb triazole), 122.9 (C4Ar), 123.2, 128.3, 128.5 (C3,5Ar),
129.9, 130.1, 130.8 (C1Ar), 130.9, 131.2, 137.0, 140.2 (Ca triazole),
6.53–6.56 (m, 1H triazole), 6.85 (d, J = 7.5 Hz, H3 or 5), 7.09–7.14 (m,
H2,6), 7.26–7.29 (m, H6′), 7.38–7.41 (m, H2′,4′,5′), 8.04 (s, NH), 8.51 (s,
NH); 13C NMR (125 MHz, DMSO-d6): 34.8 (CH2NH), 51.9 (CH2N), 54.8
(OMe), 103.5, 106.5, 110.0, 122.7, 126.5, 127.8, 127.9, 129.2, 130.5,
133.2, 138.4, 141.5 (Ca triazole), 145.9, 154.9 (C4Ar), 159.6 (CO). Anal.
calcd. for C18H18ClN5O2: C, 58.14; H, 4.88; N, 18.84. Found C, 58.29;
H, 5.01; N, 18.65.

145.9, 155.0 (C O). Anal. calcd. for C17H15Cl2N5O: C, 54.27; H, 4.02;
N, 18.61. Found C, 54.09; H, 3.89; N, 18.89.
1-((1-(2-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-3-(4-
methoxyphenyl)urea (4j)
Pale yellow solid; yield: 68%; mp: 194–196°C; IR (KBr): 3180, 1660
1-((1-(4-Chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-3-(4-
(CO) cm−1
;
1H NMR (500 MHz, DMSO-d6): 3.70 (s, OMe), 4.32 (d,
methoxyphenyl)urea (4n)
J = 5.5 Hz, CH2NH), 5.64 (s, CH2N), 6.47 (d, J = 8.0 Hz, H3 or 5), 6.52 (t,
J = 5.0 Hz, 1H triazole), 6.85 (d, J = 8.0 Hz, H3 or 5), 7.10–7.13 (m, H2,6),
7.20–7.26 (m, H3′,5′), 7.34 (t, J = 7.5 Hz, H4′), 7.39–7.42 (m, H6′), 8.04 (s,
NH), 8.51 (s, NH); 13C NMR (125 MHz, DMSO-d6): 34.7 (CH2NH), 46.7
(CH2N), 54.7 (OMe), 103.5, 106.6 (d, C3′Ar, J = 30 Hz), 110.0, 115.4,
115.6, 120.7, 122.7, 124.7, 129.2, 130.6, 133.2, 141.5 (Ca triazole),
154.7 (C4Ar), 159.3 (CO), 161.0 (d, C2′Ar, J = 249 Hz). Anal. calcd. for
Pale yellow solid; yield: 65%; mp: 181–182°C; IR (KBr): 3222, 1696
−1
;
1H NMR (500 MHz, DMSO-d6): 3.70 (s, OMe), 4.32 (d,

(C O) cm
J = 5.0 Hz, CH2NH), 5.57 (s, CH2N), 6.47 (d, J = 7.5 Hz, H3 or 5), 6.53–
6.55 (m, 1H triazole), 6.85 (d, J = 7.5 Hz, H3 or 5), 7.09–7.14 (m, H2,6),
7.33 (d, J = 7.5 Hz, H2′,6′), 7.42 (d, J = 7.5 Hz, H3′,5′), 8.00 (s, NH), 8.52 (s,
NH); 13C NMR (125 MHz, DMSO-d6): 34.8 (CH2NH), 51.8 (CH2N), 54.7
(OMe), 103.5, 106.5, 110.0, 122.7, 128.7, 129.2, 129.8, 132.7, 135.0,
141.5 (Ca triazole), 145.8, 154.9 (C4Ar), 159.6 (CO). Anal. calcd. for
C18H18FN5O2: C, 60.84; H, 5.11; N, 19.71. Found C, 60.69; H, 4.97; N,
19.58.
C18H18ClN5O2: C, 58.14; H, 4.88; N, 18.84. Found C, 57.96; H, 4.97; N,
18.99.
1-((1-(3-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-3-(4-
methoxyphenyl)urea (4k)
1-((1-(2,4-Dichlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-3-(4-
Pale yellow solid; yield: 79%; mp: 185–186°C; IR (KBr): 3190, 1659
−1
methoxyphenyl)urea (4o)
1H NMR (500 MHz, DMSO-d6): 3.69 (s, OMe), 4.32 (d,
Pale yellow solid; yield: 71%; mp: 172–174°C; IR (KBr): 3100, 1646

(C O) cm
;
−1
J = 5.0 Hz, CH2NH), 5.60 (s, CH2N), 6.47 (d, J = 7.5 Hz, H3 or 5), 6.53–
1H NMR (500 MHz, DMSO-d6): 3.70 (s, OMe), 4.32 (d,

(C O) cm ;
6.55 (m, 1H triazole), 6.85 (d, J = 7.5 Hz, H3 5), 7.09–7.15 (m,
J = 5.0 Hz, CH2NH), 5.67 (s, CH2N), 6.47 (d, J = 7.5 Hz, H3 or 5), 6.52–
6.54 (m, 1H triazole), 6.85 (d, J = 7.5 Hz, H3 or 5), 7.09–7.13 (m, H2,6),
7.25 (d, J = 8.0 Hz, H6′), 7.45 (d, J = 7.5 Hz, H5′), 7.68 (s, H3′), 7.98 (s,
NH), 8.51 (s, NH); 13C NMR (125 MHz, DMSO-d6): 34.7 (CH2NH), 49.8
(CH2N), 54.8 (OMe), 103.5, 106.5, 110.0, 122.8, 127.7, 128.4, 129.2,
129.7, 132.4, 133.5, 135.0, 141.5 (Ca triazole), 145.6, 154.9 (C4Ar),
or
H
2,6,2′,4′,6′), 7.40–7.42 (m, H5′), 8.03 (s, NH), 8.52 (s, NH); 13C NMR
(125 MHz, DMSO-d6): 34.8 (CH2NH), 52.0 (CH2N), 54.8 (OMe), 103.5,
106.6 (d, C4′Ar, J = 30 Hz), 110.0, 114.6 (d, C2′Ar, J = 25 Hz), 114.9,
122.7, 122.9, 123.9, 129.3, 130.7, 138.7, 141.5 (Ca triazole), 154.9
(C4Ar), 159.8 (CO), 162.0 (d, C3′Ar, J = 242 Hz). Anal. calcd. for

C18H18FN5O2: C, 60.84; H, 5.11; N, 19.71. Found C, 60.68; H, 5.00;
159.6 (C O). Anal. calcd. for C18H17Cl2N5O2: C, 53.21; H, 4.22; N,
N, 19.91.
17.24. Found C, 53.06; H, 4.38; N, 17.41.
1-((1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-3-(4-
1-((1-(3,4-Dichlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-3-(4-
methoxyphenyl)urea (4l)
methoxyphenyl)urea (4p)
Pale yellow solid; yield: 64%; mp: 200–202°C; IR (KBr): 3145, 1633
−1
Pale yellow solid; yield: 68%; mp: 152–153°C; IR (KBr): 3211, 1638
−1

(C O) cm
;
1H NMR (500 MHz, DMSO-d6): 3.70 (s, OMe), 4.31 (d,
1H NMR (500 MHz, DMSO-d6): 3.70 (s, OMe), 4.32 (d,

(C O) cm ;
J = 5.5 Hz, CH2NH), 5.56 (s, CH2N), 6.47 (d, J = 8.0 Hz, H3 or 5), 6.53 (t,
J = 5.5 Hz, 1H triazole), 6.85 (d, J = 8.0 Hz, H3 or 5), 7.09–7.13 (m, H2,6),
7.19 (t, J = 8.5 Hz, H3′,5′), 7.38 (t, J = 7.0 Hz, H2′,6′), 7.99 (s, NH), 8.51 (s,
NH); 13C NMR (125 MHz, DMSO-d6): 34.7 (CH2NH), 51.8 (CH2N), 54.8
(OMe), 103.5, 106.6, 110.0, 115.4 (d, C3′,5′Ar, J = 21 Hz), 122.4 (d, C2′,6′
Ar, J = 16 Hz), 129.3, 130.2, 132.3, 141.5 (Ca triazole), 145.8, 154.9
J = 6.0 Hz, CH2NH), 5.59 (s, CH2N), 6.47 (d, J = 8.0 Hz, H3 or 5), 6.54 (t,
J = 5.5 Hz, 1H triazole), 6.85 (d, J = 8.0 Hz, H3 or 5), 7.09–7.14 (m, H2,6),
7.28 (d, J = 8.5 Hz, H6′), 7.61 (s, H2′), 7.63 (d, J = 8.5 Hz, H5′), 8.04 (s,
NH), 8.51 (s, NH); 13C NMR (125 MHz, DMSO-d6): 34.7 (CH2NH), 51.2
(CH2N), 54.8 (OMe), 103.5, 106.6, 110.0, 122.7, 128.3, 129.2, 129.9,
130.1, 130.8, 133.4, 137.0, 141.5 (Ca triazole), 145.9, 154.9 (C4Ar),


(C4Ar), 159.6 (C O), 161.0 (d, C4′Ar, J = 242 Hz). Anal. calcd. for
159.6 (C O). Anal. calcd. for C18H17Cl2N5O2: C, 53.21; H, 4.22; N,
C18H18FN5O2: C, 60.84; H, 5.11; N, 19.71. Found C, 60.69; H, 5.24; N,
17.24. Found: C, 53.00; H, 4.44; N, 17.06.
19.55.
1-((1-(4-Methylbenzyl)-1H-1,2,3-triazol-4-yl)methyl)-3-(4-
1-((1-(3-Chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-3-(4-
methoxyphenyl)urea (4m)
methoxyphenyl)urea (4q)
Pale yellow solid; yield: 73%; mp: 141–142°C; IR (KBr): 3099, 1645
−1
Pale yellow solid; yield: 60%; mp: 166–168°C; IR (KBr): 3220, 1693
1H NMR (500 MHz, DMSO-d6): 2.27 (s, Me), 3.71 (s,

(C O) cm ;
(CO) cm−1
;
1H NMR (500 MHz, DMSO-d6): 3.70 (s, OMe), 4.32
OMe), 4.30 (d, J = 5.0 Hz, CH2NH), 5.50 (s, CH2N), 6.47 (d, J = 8.0 Hz,
(d, J = 5.0 Hz, CH2NH), 5.597 (s, CH2N), 6.47 (d, J = 7.5 Hz, H3 or 5),
H3′ 5′), 6.52–6.54 (m, 1H triazole), 6.85 (d, J = 8.0 Hz, H3′ 5′),
or
or

MOGHIMI ET AL.
7 of 8
|
7.09–7.13 (m, H2′,6′), 7.16 (d, J = 7.5 Hz, H3′,5′), 7.21 (d, J = 7.5 Hz,
site characterization. Afterwards, polar hydrogens and rotatable bonds
were added by AutoDock Tools (1.5.6, ADT), respectively. In addition,
the preparation of input files was performed by graphical user
interface AutoDock Tools. 2D and 3D ligand–receptor interactions
were evaluated by Ligplot+ version v.1.1.0 program[50] and Discovery
Studio v.3.5.[51] Docking studies were carried out by maximum number
of 25 × 106 energy evaluations. After clustering analysis, the best
conformation with the most sensible binding energy was obtained.
H
2′,6′), 7.93 (s, NH), 8.49 (s, NH); 13C NMR (125 MHz, DMSO-d6): 20.5
(Me), 34.7 (CH2NH), 52.5 (CH2N), 54.8 (OMe), 103.5, 106.5, 110.0,
122.4, 127.9, 129.2, 129.9, 133.0, 137.3, 141.5, 145.7, 154.9 (C4Ar),
159.6 (CO). Anal. calcd. for C19H21N5O2: C, 64.94; H, 6.02; N, 19.93.
Found: C, 64.70; H, 5.84; N, 19.78.
|
4.2 Biological evaluation
All chemicals and jack bean urease (EC 3.5.1.5) were purchased from
Sigma–Aldrich (USA) and other commercial sources. Ultra-pure water
(HPLC grade; Duksan, Korea) was utilized in all experiments. Potassium
phosphate buffer solution (100 mM), pH 7.4, was prepared in distilled
water. The absorbance spectra were recorded on a Synergy H1 Hybrid
multi-mode microplate reader (BioTek, Winooski, VT, USA).
ACKNOWLEDGMENT
This study was funded and supported by the research council of the
Institute of Pharmaceutical Sciences (TIPS); Tehran University of
Medical Sciences (TUMS); Grant no. 97-01-45-37514.
Urease inhibitory assays of the synthesized compounds were
evaluated at the concentration of 0–10 mg/mL, using the modified
Berthelot spectrophotometric method at 625 nm. The obtained results
were compared with the standard compounds, hydroxyurea and
thiourea.[46,47]
CONFLICT OF INTEREST
The authors declare no conflict of interest.
ORCID
The enzymatic reactions were performed in phosphate buffer
(100 mM, pH 7.4) solution which reach to the 985 µL by adding urea
(850 µL) and the synthesized compound (100 µL, 0–10 mg/mL). Then,
after the addition of the urease enzyme (15 µL), the concentration of
liberated ammonia was measured after 60 min. The corresponding
concentration of ammonia was obtained by addition of incubated
solution (100 µL) to the mixture of solution A (500 µL, containing 5.0 g
phenol and 25.0 mg sodium nitroprusside in 500 mL distilled water)
and solution B (500 µL, containing 2.5 g sodium hydroxide and 4.2 mL
sodium hypochlorite (5% chlorine) in 500 mL distilled water) which was
incubated at 37°C for 30 min. The absorbance was determined by
measuring indophenols at 625 nm. The activity of uninhibited urease
was considered as the control activity of 100%. The inhibition studies
were conducted according to this formula: I (%) = [1 − (T/C)] × 100;
where I (%) is the inhibition of the enzyme, T (test) is the absorbance of
the evaluated sample (analyzed compounds) in the presence of
enzyme, and C (control) is the absorbance of the solvent in the
presence of enzyme. Data were expressed as mean standard error
(SD) and run in triplicate. The values of IC50 for all analyzed compounds
Alireza Foroumadi
http://orcid.org/0000-0003-2416-5611
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How to cite this article: Moghimi S, Goli-Garmroodi F,
Allahyari-Devin M, et al. Synthesis, evaluation, and molecular
docking studies of aryl urea-triazole-based derivatives as
anti-urease agents. Arch Pharm Chem Life Sci. 2018;1–8.
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