Novel and versatile methodology for synthesis of β-aryl-β- mercapto ketone derivatives as potential urease inhibitors

Article abstract of DOI:10.1007/s13738-013-0379-1

The objective was to obtain new scaffold of compounds possessing anti-urease activity. For this new and simple method for the synthesis of β-aryl-β-mercapto ketone derivatives based on Michael addition of thiophenol to chalcones in an ionic liquid as a so

Full text of DOI:10.1007/s13738-013-0379-1

J IRAN CHEM SOC
DOI 10.1007/s13738-013-0379-1
ORIGINAL PAPER
Novel and versatile methodology for synthesis of b-aryl-b-
mercapto ketone derivatives as potential urease inhibitors
•
Mohammad Mahdi Ahari-Mostafavi
•
Ali Sharifi Mojtaba Mirzaei Massoud Amanlou
•
Received: 23 April 2013 / Accepted: 7 November 2013
Ó Iranian Chemical Society 2013
Abstract The objective was to obtain new scaffold of
compounds possessing anti-urease activity. For this new
and simple method for the synthesis of b-aryl-b-mercapto
ketone derivatives based on Michael addition of thiophenol
to chalcones in an ionic liquid as a solvent was improved.
The products were obtained in good to moderate yields
with high purity and characterized by spectral and ele-
mental analyses. The activities of synthesized compounds
were investigated as new inhibitors of jack bean urease.
Among 22 synthesized compounds, all of them have shown
inhibitory effect in micromolar range, and the most potent
Introduction
The most widespread nickel metalloenzyme is urease (EC
3.5.1.5), which is an important enzyme in both agriculture
and medicine [1, 2]. The two nickels were coordinated by
His407, His409, Kcx490, His519, His545, and Asp633 in its
active site [3]. It can hydrolyze urea which is an end product
of the catabolism of nitrogen-containing compounds to
form eventually ammonia and carbon dioxide [4].
Pathogenicity of Helicobacter pylori indicates that
ammonia generated by urease on urea can cause injury to
the gastroduodenal mucosa and helps bacteria to endure in
the acidic pH of the stomach during colonization [5, 6].
Consequently, approaches based on specific inhibition of
urease are the main treatment and eradication caused by
this large heteropolymeric enzyme [7].
one has IC50 = 6 lM compared to hydroxyurea IC50
=
100 lM as a reference inhibitor. A docking study was
performed using Autodock 4.2 in parallel to in vitro
experiments to illustrate the corresponded binding affinities
as well as binding site, and involved residues in interaction.
These computational results complimented the experi-
mental inhibition activity and enabled us to report a potent
urease inhibitors based on b-aryl-b-mercapto ketone
scaffold.
Recently, some complexes of Schiff bases showed a
significant inhibitory activity against urease [8, 9]. In this
regard, Chalcone derivatives have various therapeutic
properties including antioncogenic [10], antiinflammatory
[11], antitumor [12], antileishmanial [13], antifungal [14],
and antiulcer [15] effects. Furthermore, it is reported that
different enzymes inhibitors and antioxidants are designed
based on chalcones [16–18]. Therefore, synthesis of such
compounds is of great interest in view of variety of phar-
macological properties. In the following, by undertaking a
new procedure in synthesized saturated chalcons, b-aryl-b-
mercapto ketones, we tried to explore novel inhibitors,
which have better inhibition potency through urease. In
recent years, inhibitors have been designed based on
choosing the appropriate pharmacophoric groups [19–21].
Therefore, to obtain the precise three-dimensional struc-
tural information and better understanding of modes of
interactions, a molecular docking study was performed and
related pharmacophore was generated.
Keywords b-Aryl-b-mercapto ketone ꢀ Urease
inhibitors ꢀ Molecular docking
Electronic supplementary material The online version of this
article (doi:10.1007/s13738-013-0379-1) contains supplementary
material, which is available to authorized users.
M. M. Ahari-Mostafavi ꢀ A. Sharifi ꢀ M. Mirzaei
Chemistry and Chemical Engineering Research Center of Iran,
14335-186 Tehran, Iran
M. Amanlou (&)
Department of Medicinal Chemistry, Faculty of Pharmacy and
Drug Design and Development Research Center, Tehran
University of Medical Sciences, 14155-6451 Tehran, Iran
e-mail: amanlou@tums.ac.ir
123

J IRAN CHEM SOC
Experimental works
oftheenzyme, sonicationwasperformedfor60 s,followedby
centrifugation and evaluation of the absorbance of upper
solution in k = 280 nm (Cecil-UV 9000) which is attributed
to the enzyme. By using the following equation A ¼ ebc
where c istheconcentration ofsolution(mol/L), b isthe length
of the UV cell, and e represents molar absorptivity in the
specific wavelength, we could calculate the concentration of
initially urease solution. After proper dilution, the concen-
tration of enzyme solution was 2 mg/ml.
Materials
TLC experiments were performed on pre-coated silica gel
plates using EtOAc/hexane (1:4) as the eluent. Melting
points were reported without correction. IR spectra were
recorded using KBr disks on a Shimadzu IR Prestige-21
infrared spectrophotometer. HNMR (125 MHz) and 13C
1
NMR (500 MHz) spectra were recorded on a FT-NMR
Bruker Ultra ShieldTM as CDCl3 solutions using TMS as
internal standard reference. Mass spectra were obtained on a
Fisons Trio 1000 instrument at ionization potential of 70 eV.
Elemental analyses were performed using a Thermo Finni-
gan Flash EA 1112 instrument. Solvents and reagents were
purchased from commercial sources. Different ionic liquids
were prepared using known procedures [22, 23]. Also, the
chalcone derivatives were prepared using Diels–Alder
condensation. Known products were identical with authentic
samples by melting points, TLC, and NMR determinations
[24–35]. New product was characterized based on their
1HNMR, 13CNMR, IR, and mass spectra and their purity
was confirmed by elemental analysis (supplementary data).
Enzyme inhibition assay
Urease activity was determined by measuring the release of
ammonia by a modification of the Berthelot reaction [36].
The reaction mixture contained 50 mM urea, 100 ll
(2 mg/ml) of JBC, and 100 ll of the test compounds of var-
ious concentrations in 100 mM sodium phosphate buffer (pH
7.6). After pre-incubation for 30 min at 37 °C, the reaction
was terminated by addition of 500 ll of 0.5 % phenol—
0.0025 % sodium nitroprusside solution. Then, 500 ll of
0.25 % sodium hydroxide—0.21 % sodium hypochlorite
solution was added, the mixture was incubated for 30 min at
37 °C for color development. This method is based on the
released ammonia (NH3) which reacts with hypochlorite
(OCl-) to form a monochloramine and the absorbance at
625 nm was determined. Urease activity of control was taken
as 100 % and enzyme inhibition is expressed as % inhibition.
All the results were of triplicate run.
Chemistry
General and typical procedure synthesis of b-aryl-b-
mercapto ketone derivatives
The general procedure is as follows: a mixture of [omim][Cl]
(3 mmol, 0.7 gr), thiol 2 (1 mmol), chalcone derivative 12
(1 mmol), and water (0.5 ml) was stirred vigorously at room
temperature. The reaction mixture was allowed to stir until the
color changed from yellow to white (monitored by TLC and
assisted by visual observation). The mixture was extracted
with ethyl acetate (3 9 10 mL), and the combined ethyl
acetate extract was washed with brine, dried (Na2SO4), and
evaporated to leave the crude product. The crude product was
purified by recrystallization in ethanol.
Protocol of docking study
Computational resources
The computational studies were carried out on a computer
cluster comprising four sets of HP Prolient ML370-G5
tower servers equipped with two quad-core Intel Xeon
E5355 processors (2.66 GHz) and 4 GB of RAM, running
a Linux platform (SUSE 10.2). Linux version of Molecular
Graphics Laboratory Tools (MGLTools, 1.4.5), Auto-
DockTools (ADT), Autogrid4.2, and Autodock4.2 were
downloaded from http://www.scripps.edu [37]. ADT was
employed to set up the enzymes and ligands input files and
viewing docking log files. Autogrid4.2 [37] and Auto-
dock4.2 [37] were used to calculate grid box and docking
experiments.
Biological assay
Jack bean urease (8 units/mg), phenol, and sodium nitro-
prusside were obtained from Sigma. Urea, sodium
hydroxide, sodium dihydrogen phosphate, and sodium
hydrogen phosphate were purchased from Merck and used
without purification. All aqueous solutions were prepared
in MilliQ water (Millipore, USA).
Protein preparation for docking
The crystal structure (3D structure) of urease enzyme with
˚
resolution of 2.05 A was downloaded from the Brookhaeven
Total protein assay
protein data bank (3LA4, http://www.pdb.org) and was used
for docking studies. In the present study, non-standard pro-
tein residues (KCX and CME) and the metal ions were
For urease inhibition assays, after addition of 10 mL of
phosphate buffer, in order to obtain the accurate concentration
123

J IRAN CHEM SOC
included in the binding site specification but before initiating
the docking simulations, all other non-protein molecules
(ligand and all water molecules) were removed from struc-
ture file [21, 38]. To prepare the urease structure for docking,
polar hydrogen’s, Kollman united atom charges, and solva-
tion parameters were added using ADT and then kept rigid in
the docking process, whereas all the torsional bonds of
ligands were set free by Ligand module in ADT or using the
prepare_receptor4.py script [37].
Results and discussion
Chemistry
Each synthesis procedure has several drawbacks such as low
yield, being time-consuming and using expensive catalysts.
In the present work, we investigated the use of room tem-
perature ionic liquids as catalytic and environmentally
benign solvents for the facile homogenous synthesis of a
series of substituted b-aryl-b-mercapto ketone without the
use of any base or any special activation (Scheme 1). From
the synthetic point of view, b-aryl-b-mercapto ketones are
useful key steps in the synthesis of pharmaceutical com-
pounds [39–43]. Therefore, the synthesis of b-aryl-b-mer-
capto ketone has attracted much attention in organic
synthesis. In our continuing effort to evaluate these com-
pounds inhibitory effect on urease, we were interested in
utilizing ionic liquids as an environmentally attractive
medium to develop new methodologies for the synthesis.
There are several reports in the literature for thia-
Michael addition utilizing ZrCl4–SiO2 [44], InCl3 [45],
Cu(BF4)2ꢀH2O [46], Zn(ClO4)2 [47], and NaOH [48], hy-
drotalcites [49]. The Michael addition has attracted enor-
mous attention as one of the most important sulfur–carbon
bond forming reactions in organic synthesis [50]. These
have generated interest to develop new methodologies for
thia-Michael addition reaction for synthesis of some b-
aryl-b-mercapto ketone derivatives. In order to substantiate
the concept, all b-aryl-b-mercapto ketone derivatives
studied were generated from 1,4-conjugate addition of a
thiol to a chalcone derivatives via a thia-Michael addition
in an ionic liquid at ambient temperature with an equimolar
amounts of thiol and chalcone to afford the corresponding
b-aryl-b-mercapto ketone derivatives (Table 1).
Ligand preparation for docking
All synthesized compounds (ligands) and thiourea were
built by Marvin sketch applet (Marvin package, Chemaxon
Company) and optimized using ‘‘Prepare Ligands’’ script
in the ADT for docking studies. The ligand structures were
prepared for docking by merging non-polar hydrogen
atoms, adding Gasteiger partial charges, and defining
rotatable bonds. The optimized ligand molecules were
docked into urease model using Autodock4.2. The resulting
docked poses with root mean square deviation values
˚
(RMSD) \2 A were clustered together and the lowest
energy minimized pose was used for further analysis. The
best conformation of each of the ligand–urease complex
was selected based on docking energy [37].
Docking parameters
In general, following parameters were used for docking
simulations: the size of the docking grid was 40 9 40 9 40
˚
A points around active site of urease, The centre of the grid
was set to the average coordinates of the two Ni2? ions in
the a chain of urease. The initial population size
(ga_pop_size) was 150, and the maximum number of
energy evaluations (ga_num_evals) was 25 9 106, max-
imum number of generations (ga_num_generations) was
27,000 and the number of Autodock Lamarckian genetic
algorithm local search run jobs (ga_run) was 100. All other
parameters were set to their default settings. On successful
completion of docking, clustering analysis was performed
and a conformation with the most favorable binding energy
was selected. This protocol was then similarly applied to all
synthesized compounds [21, 37, 38].
The reaction was optimized for preparation of 21 using
4-methoxychalcone with thiophenol in eight different
ionic liquids, which were prepared in our laboratory
(Table 2). Also, due to the high viscosity of some ionic
liquids, a proper amount of water was added to control
the mixing conditions. The results showed that the
1-octyl-3-methylimidazolium chloride [omim][Cl] would
be the best ionic liquid for this reaction according to the
obtained yield.
Scheme 1 Synthesis of series
of substituted b-aryl-b-mercapto
ketones
R3
O
O
S
[omim]Cl
H2O , rt
HS R3
+
R1
R2
R1
R2
1
3
2
R1 : H, Me, OH, R2 : H, Cl, OMe, R3 : Ph, Naphthyl, Octyl, 4-Cl-Phenyl, Benzyl, 2-AminoPhenyl,
2-Furylmethyl, 4-AminoPheny
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J IRAN CHEM SOC
Table 1 Structure and physical properties of b-aryl-b-mercapto ketones derivatives
(C Ring) R1
S
R3 (Ring A)
O
R2 (Ring B)
Entry
R1
R2
R3
Time (min)
Isolated yield (%)
1
H
4-Methyl-Phenyl
4-Methoxy-Phenyl
2-Nitro-Phenyl
4-Cl-Phenyl
Phenyl
2-AminoPhenyl
2-AminoPhenyl
2-AminoPhenyl
2-AminoPhenyl
2-AminoPhenyl
2-AminoPhenyl
2-AminoPhenyl
4-AminoPhenyl
2-AminoPhenyl
Phenyl
15
10
15
5
91
98
95
95
90
90
90
93
91
97
94
97
93
63
97
94
95
92
90
90
90
95
2
4-Methoxy-Phenyl
3
H
4
H
5
H
10
25
30
5
6
H
4-Methoxy-Phenyl
4-Nitril-Phenyl
Phenyl
7
H
8
H
9
H
4-F-Phenyl
H
5
10
11
12
13
14
15
16
17
18
19
20
21
22
OH
OH
H
5
H
Furane
15
5
Phenyl
Phenyl
H
Phenyl
Methyl-furan
Benzyl
15
8
H
Phenyl
H
4-Cl-Phenyl
Phenyl
Benzyl
6
H
Naphthyl
15
15
29
25
20
25
5
CH3
H
Phenyl
Naphthyl
4-Methoxy-Phenyl
Phenyl
Benzyl
H
Octyl
H
4-Methoxy-Phenyl
4-Methoxy-Phenyl
4-Cl-Phenyl
4-Cl-Phenyl
Phenyl
H
H
Phenyl
Table 2 Different types of used ionic liquids in synthesized of
compound 21
to H. pylori urease in its structure. Under the same con-
dition, most of compounds showed potent urease inhibitory
activities, compared with that of the standard inhibitor
hydroxyurea, which had IC50 of 100 lM [51] as shown in
Table 3.
Entry
ILs
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
[omim]BF4
[bmim]BF4
[omim]Cl
[omim]NO3
[Hmim]I
50
50
50
50
50
50
50
50
85
75
95
93
60
55
50
60
According to Table 3, compound 3 shows the most
potent inhibition through urease which is illustrated in
Fig. 1. In this series, which consists of nine compounds
(1–9), ring A contains amino group in different positions.
As it illustrate shifting of amino group from ortho- (5,
IC50 = 56 lM) to para- (8, IC50 = 127 lM) position
deprive inhibitory effect since not only make some steric
hindrance, but also NH2 group places as far as Asn168
[omim]N(CN)2
[bmim]PF6
[bpy]BF4
˚
(5 A) to make hydrogen binding in site of interaction. On
Urease inhibition assays (in vitro)
the other hand, substituent of Cl and F group in ring B of
4 and 9, respectively, result in different activities. Com-
pound 9 in comparison with 6 and 1 (IC50 = 63 and
28 lM, respectively) has IC50 = 16 lM. Moreover, it
shows better affinity according to DG° values
(-8.3 kcal mol-1) to binding site when it has been
The order of amino acids and their enzymatic mechanism
in urease were preserved. So, in order to evaluate synthe-
sized compounds inhibitory effects, biological experiments
of all b-aryl-b-mercapto ketone derivatives were assessed
against urease from jack bean which has [80 % similarity
123

J IRAN CHEM SOC
compared with 4 (DG° = -7 kcal mol-1) (Table 3). This
effect could be due to better stabilization of compound in
site and closer interactions with His 274 and 138 residues.
Besides, according to docking studies Met 366 positions
other substituent on ring B different derivatives has been
synthesized. Inserting electron with drawing nitro group
in ortho-position of 3, result in binding free energy equal
to -10.18 kcal mol-1 (Table 3). This effect partially
diminishes in 2, which two electron donning methoxy
groups have been inserted in para-position of rings B and
C. Although this compound has bulkier groups, strong
interaction of S and Met 366 has significant effect in its
inhibition power. At last in this series, nitrile substitution
in para-position of ring B as electron withdrawing group
result 7 with IC50 = 18 lM that can be conclude, electron
donning and withdrawing substituent on rings A and B,
respectively, cause compounds with better inhibition
which can be used as scaffold for next optimizations.
In the next modification, hydroxyl group has been
substituted in para-position of ring C. Urease inhibition has
been increased in 10 (IC50 = 35 lM) in contrast with un-
substitute one (12 with IC50 = 5 lM). Better inhibition by
para-substitution of electron donning group previously has
been approved in compound 2. In this group, ring A has
been replaced by furan ring, 11. Juxtaposition of electron
withdrawing group such as furan to sulfur atom of com-
pounds, deplete charge on sulfur and result better hydrogen
interaction. According to docking studies, 11 is entered to
active site binding pocket through hydroxyl group similar
to 10. For more insight to importance of nature of ring A
and its distance to S atom, derivatives 13–18 have been
synthesized. In all compounds, longer distances decrease
inhibition potency, but this effect cover by inserting aro-
matic group, phenyl, instead of methyl as just hydrophobic
group, 16 (IC50 = 16 lM) and 14 (IC50 = 151 lM),
respectively. Indeed, enzyme inhibition was enhanced
when the phenyl-carrying ligand was replaced by the
naphthyl moiety. Observed inhibition may be due to the
conformational change of urease by phenolics [52]. On the
other hand, in 13 a phenyl ring has been replaced by furan
in longer distance. This results in diminishing H-bond
formation between thiol atom of 11 and near amino acids
because of inappropriate placement in site. By the way, in
˚
in 3.4 A of ring B that causes p–p interaction between
sulfur atom of amino acid and ring. For investigation,
Table 3 Binding energy, final intermolecular, electrostatic energy
from docking studies, and inhibitory activity of b-aryl-b-mercapto
ketones derivatives against Jack bean urease
Compound Binding
energy
Final
intermolecular
Electrostatic
energy (Kcal/ (lM)
mol)
IC50
(Kcal/mol) energy (Kcal/
mol)
1
-7.76
-8.48
-10.18
-7.00
-7.43
-7.02
-8.15
-6.90
-8.30
-7.59
-7.66
-7.02
-6.91
-6.90
-7.02
-7.98
-8.40
-6.73
-6.65
-7.20
-6.84
-6.57
-5.39
-8.15
-9.25
-11.60
-8.32
-9.16
-9.31
-8.94
-8.57
-8.98
-9.50
-8.77
-8.46
-8.56
-8.68
-8.82
-9.38
-9.81
-8.87
-8.78
-9.22
-8.81
-8.18
-6.17
-0.04
-0.32
-4.54
-0.08
-0.90
-1.40
-0.88
-0.75
-1.54
-1.80
-1.94
-0.74
-0.25
-0.37
-0.09
-0.67
-0.73
-0.08
-0.00
-1.76
-1.68
-0.68
-0.73
28
12
2
3
6
4
102
56
5
6
63
7
18
8
127
9
16.6
10
11
12
13
14
15
16
17
18
19
20
21
22
Std
35
25
85
83
151
97
16.3
14
167
125
71
135
181
100
Std hydroxyurea
Fig. 1 Interaction diagram of
the docked conformer of
compound 3 with the active site
residues of the enzyme.
a Represented inhibitor
perfectly fit into the enzyme
active site. b Residues that are
involved with interaction are
demonstrated
123

J IRAN CHEM SOC
13 hydrophobic interactions between additional methyl
group and Ala169 partially improve potency In comparison
with 14 with bulkier phenyl group, which causes steric
hindrance. 17 in comparison with its relative structure, 16,
demonstrate moderately improvement in inhibition potency
due to additional hydrophobic interaction of methyl group
in para-position and hydrophobic pocket that has been
confirmed by docking studies. The bonding energy of
earlier has been estimated -8.4 kcal mol-1. Finally,
effects of different substituent’s have been studied by
evaluate inhibition power of 15 and 18. Both compounds
have penetrated to the entrance of urease active site from
ring C, but 15 have penetrated more effectively and shows
DG° = -7.02 kcal mol-1 (Table 3). This part could be
more modified by chain groups, which make better diffu-
sion of compound to active site without steric hindrance.
This modification with lower efficiency is illustrate by
evaluating inhibition potency of compound 19 which
shows IC50 = 125 lM. Computational studies raveled that
19 (DG° = -6.65 kcal mol-1) has been oriented trough
active site from alkyl chain. Lower binding affinity of this
compound may due to deleting aromatic ring A in contrast
to 12 and 16. On the other hand, proper orientation of
chlorine in 15 causes hydrophobic interaction with Ala 169
which has been missed in 18.
inhibition among all. The binding pattern of this potential
inhibitor which is localized in active site could help us to
understand its inhibitory activity. Scaffold of b-aryl-b-
mercapto ketone urease inhibitors can be utilized in further
optimization to improve potency and selectivity by varia-
tions in the basic skeleton.
Acknowledgments The financial supports of the Research Council
of the Tehran University of Medical Science, and Deputy of Research
of Chemistry and Chemical Engineering Research Center of Iran are
gratefully acknowledged.
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