Synthesis, Density functional theory (DFT), Urease inhibition and antimicrobial activities of 5-aryl thiophenes bearing sulphonylacetamide moieties

Article abstract of DOI:10.3390/molecules201119661

A variety of novel 5-aryl thiophenes 4a-g containing sulphonylacetamide (sulfacetamide) groups were synthesized in appreciable yields via Pd[0] Suzuki cross coupling reactions. The structures of these newly synthesized compounds were determined using spec

Full text of DOI:10.3390/molecules201119661

Article
Synthesis, Density Functional Theory (DFT), Urease
Inhibition and Antimicrobial Activities of 5-Aryl
Thiophenes Bearing Sulphonylacetamide Moieties
1
1,
1
1
2
Mnaza Noreen , Nasir Rasool *, Yasmeen Gull , Muhammad Zubair , Tariq Mahmood ,
2
3
3
4
Khurshid Ayub , Faiz-ul-Hassan Nasim , Asma Yaqoob , Muhammad Zia-Ul-Haq and
5
,
Vincenzo de Feo *
Received: 19 August 2015 ; Accepted: 23 October 2015 ; Published: 5 November 2015
Academic Editor: Derek J. McPhee
1
Department of Chemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan;
mnazanoreen@yahoo.com (M.N.); yasmeenchem1@yahoo.com (Y.G.); zubairmkn@yahoo.com (M.Z.)
Department of Chemistry, COMSATS Institute of Information Technology, University Road, Tobe Camp,
2
Abbottabad 22060, Pakistan; mahmood@ciit.net.pk (T.M.); khurshid@ciit.net.pk (K.A.)
Department of Chemistry, The Islamia University of Bahawalpur, Bahawalpur 63000, Pakistan;
3
faiznasim@hotmail.com (F.-H.N.); asmayaqoobctn@gmail.com (A.Y.)
The Patent Office, Karachi 74200, Pakistan; ahirzia@gmail.com
Department of Pharmaceutical and Biomedical Sciences, University of Salerno, Via Ponte don Melillo,
4
5
Fisciano (Salerno) I-84084, Italy
*
Correspondence: nasirrasool@gcuf.edu.pk (N.R.); defeo@unisa.it (V.F.); Tel.: +92-332-7491790 (N.R.);
Fax: +92-41-9201032 (N.R.)
Abstract: A variety of novel 5-aryl thiophenes 4a–g containing sulphonylacetamide (sulfacetamide)
groups were synthesized in appreciable yields via Pd[0] Suzuki cross coupling reactions. The
structures of these newly synthesized compounds were determined using spectral data and
elemental analysis. Density functional theory (DFT) studies were performed using the B3LYP/6-31G
(d, p) basis set to gain insight into their structural properties. Frontier molecular orbital (FMOs)
analysis of all compounds 4a–g was computed at the same level of theory to get an idea about
their kinetic stability. The molecular electrostatic potential (MEP) mapping over the entire stabilized
geometries of the molecules indicated the reactive sites. First hyperpolarizability analysis (nonlinear
optical response) were simulated at the B3LYP/6-31G (d, p) level of theory as well. The compounds
were further evaluated for their promising antibacterial and anti-urease activities. In this case, the
antibacterial activities were estimated by the agar well diffusion method, whereas the anti-urease
activities of these compounds were determined using the indophenol method by quantifying
the evolved ammonia produced. The results revealed that all the sulfacetamide derivatives
displayed antibacterial activity against Bacillus subtiles, Escherichia coli, Staphylococcus aureus,
Shigella dysenteriae, Salmonella typhae, Pseudomonas aeruginosa at various concentrations. Furthermore,
the compound 4g N-((5-(4-chlorophenyl)thiophen-2-yl)sulfonyl) acetamide showed excellent urease
inhibition with percentage inhibition activity ~46.23 ˘ 0.11 at 15 µg/mL with IC50 17.1 µg/mL.
Moreover, some other compounds 4a–f also exhibited very good inhibition against urease enzyme.
Keywords: sulfacetamide; Suzuki cross coupling reactions; urease activity; antibacterial activity;
DFT; frontier molecular orbitals (FMOs) analysis; MEP; hyperpolarizability and non-linear optical
(NLO) properties
Molecules 2015, 20, 19914–19928; doi:10.3390/molecules201119661
www.mdpi.com/journal/molecules

Molecules 2015, 20, 19914–19928
1
. Introduction
N-acylsulfonamide (sulfacetamide) is well known basic common structural motif [1],
which is present as a functional group in a wide range of therapeutics [2]. The formation
of N-acylsulfonamides (sulfacetamides) is synthetically important for easy access to various
structures [3]. Molecules containing acylsulfonamide (sulfacetamide) functional groups have been
explored as HCV protease inhibitors and CXCR antagonists [4]. Moreover aryl sulfonamides are
2
potential therapeutic agents in a number of pharmaceutical patents with a wide range of biological
activities [5]. The N-acylsulfonamide (sulfacetamide) moiety has great importance in drug chemistry
due to its various biological activities. Sulfonamide –SO NH– bearing compounds are biologically
2
active [6]. Therefore, we focused on the synthesis of 5-bromothiophene-2-sulfonamide followed by
the N-acylation of 5-bromothiophene-2-sulfonamide followed by Suzuki cross coupling to obtain
various 5-arylthiophene-2-sulfonylacetamide derivatives. The inspiration of this work was the very
little attention paid tothe Pd[0] catalyzed Suzuki cross coupling reactions of N-acylsulfonamides
(sulfacetamides). The major advantages of the Suzuki cross coupling reaction compared to other
coupling reactions is the ready availability of different aryl boronic acids/esters [7]. Moreover, these
reactions can be carried out under mild conditions compared to other organometallic reactions [1].
1
13
The newly synthesized compounds were isolated and characterized by H-NMR, C-NMR and
mass spectrometry [8,9]. Moreover, these compounds were investigated for their structure activity
relationship by using density functional theory (DFT), and evaluated for urease inhibition and
antibacterial activities.
2
. Results and Discussion
2
.1. Chemistry
Herein, we report the synthesis of a series of new 5-bromothiophene-2-sulphonylacetamidesderivatives
4
a–g by the application of Suzuki cross coupling reactions [10]. To the best of our knowledge, there
are only a few reports describing the N-acylation of sulfonamides under acidic condition [11] and
Suzuki cross coupling reaction of 5-bromothiophene-acylsulfonamide (sulfacetamide). To carry out
the synthesis, we started with the preparation of 5-bromothiophene-2-sulfonamide (2) by reaction
of 2-bromo-thiophene with chlorosulfonic acid and PCl , followed by the addition of ammonia as
5
reported previously [12] (Scheme 1).
ClSO H, CCl
O
3
4
Br
Br
S NH2
o
S
-
25 C, 30 min
S
1
O
2
aq-NH3
Scheme 1.
Synthesis of 5-bromothiophene-2-sulfonamide (2).
Reagents and conditions:
Bromothiophene (12 mmol), chlorosulfonic acid (40–60 mmol), solvent (CCl , 6 mL).
4
Furthermore, we synthesized N-((5-bromothiophen-2-yl)sulfonyl)acetamide (sulfacetamide)
3, Scheme 2) by reacting 2 with acetic anhydride in acetonitrile in the presence of few
(
drops of sulfuric acid by using method described by Martin et al. [1]. The Suzuki reaction of
N-((5-bromothiophen-2-yl)sulfonyl)acetamide (3, 0.704 mmol) with 0.774 mmol of different aryl
boronic acids and boronic esters gave 5-arylthiophene-2-sulfonylacetamides 4a–g in moderate to very
good yields (Table 1) [13].
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Molecules 2015, 20, 19914–19928
Scheme 2. Synthesis of 5-bromothiophene-2-sulfonyl acetamide (3). Reagents and conditions: (i) 2
(0.002 mmol), acetic anhydride (0.0031 mmol), acetonitrile (5 mL); (ii) 3 (0.704 mmol), aryl boronic
acids or arylboronic acid pinacol esters (0.774 mmol), K PO (1.409 mmol), Pd (PPh ) (5 mol %),
3
4
3 4
˝
solvent/H O (4:1), (see Table 1), 90 C, 30 h.
2
Table 1. Synthesis of 5-arylthiophene-2-sulfonylacetamide 4a–g.
Entry
Reagent
Product
Solvent/H O (4:1)
Yields% a
2
1
1,4-Dioxane
Toluene
77
2
3
68
66
1,4-Dioxane
4
5
1,4-Dioxane
1,4-Dioxane
68
72
O
HN
O
S
O
S
4
CH
3
d
6
1,4-Dioxane
74
O
S
HN
O
O
S
7
8
1,4-Dioxane
1,4-Dioxane
70
65
S
4
f
CH3
a
˝
Isolated yield conditions: (95 C, 30 h). The yields summarized in Table 1 are based on one time Suzuki cross
coupling reaction.
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Molecules 2015, 20, 19914–19928
In this context, we first focused our work on the optimization of the reaction
conditions by studying the effect of solvent, base, catalyst and reflux time. It was noted
that 5-bromothiophene-2-sulfonylacetamide (3, 0.704 mmol) reacted with phenyl boronic ester
(
0.774 mmol) in the presence of base K PO4 (1.409 mmol), and Pd(PPh3)4 (5 mol %) in
3
aqueous 1,4-dioxane (4:1 solvent/water ratio) to give a 77% yield of desired product 4a
˝
after refluxing at 90 C for 30 h (Table 1). Furthermore, the Pd[0] catalyzed reaction of
N-((5-bromothiophen-2-yl)sulfonyl)acetamide (3, 0.704 mmol) with similar phenyl boronic esters
˝
(
(
0.774 mmol) in toluene-water (4:1 solvent/water ratio) at 90 C for 30 h in the presence of Pd
PPh ) (5 mol %) as a catalyst, to afford a moderate yield (64%, Table 1) of the desired product 4a.
3
4
It was noted that Pd[0] Suzuki cross coupling reactions of 3 with 3,5-methyl-ditrifluoromethylphenyl
boronic ester, 3,4-dichlorophenyl boronic acid and 4-chlorophenyl boronic acid (0.774 mmol) afforded
the desired compounds 4b, 4c and 4g in 66%, 68% and 65% yields, respectively (Table 1). In contrast,
we observed that the reaction of 3 with 4-methylphenyl boronic acid, 3,5-dimethyl-phenyl boronic
acid and 5 methylthiopheneboronic in the presence of 1,4-dioxaneand K PO (1.409 mmol) as a base
3
4
and 5 mol % (tetrakis)Pd as catalyst successfully gave products 4d, 4e and 4f in 72%, 74% and 70%
yields, respectively (Table 1).
It was noted that the electron rich and electron poor aryboronic acids and esters had a great
effect on the Pd[0] catalyzed Suzuki coupling reaction and the yields of the desired products. In
these reactions, the base first converts the boronic acids and boronic esters into boronate ion, which
is transmetallated faster than neutral boronic acid. The selectivity of this process is based on the
fact that the boronate ion is a superior nucleophile and fastly replaces bromide ion in the Pd(II)
(intermediate) complex [14]. For structure determination, the protons of the phenyl and thiophene
rings of 4a–g having electron donating and withdrawing functionality exhibited a chemical shift
range of δ 7.90–6.97 ppm, while the protons of the amide functionality showed chemical shift values
in range of δ 8.77–8.44 ppm. Further confirmation of the structures 4a–g allowed assignment of the
1
singlet peak appearing at δ 2.09–2.12 ppm to the 3H of the acetyl group, respectively. The H-NMR
and mass spectra of compounds 4c and 4e are provided in the Supplementary Materials.
2
.2. DFT Studies
2
.2.1. Geometry Optimization
Nowadays computational based methods have become very popular to investigate the
structure-activity relationships of compounds and density functional theory (DFT) study is one of
the most widely used computational methods due to its accuracy and less time consumption. The
energy minima geometries of all products 4a–g were optimized using the Gaussian 09 program
at the B3LYP/6-31G (d, p) level of DFT. Optimized geometries were further used for structural
investigations like frontier molecular orbitals analysis (FMOs), electrostatic potential (ESP) mapping
and nonlinear optics (NLO) properties measurement.
2
.2.2. Frontier Molecular Orbital (FMO) Analysis
FMO analysis using computational methods is widely employed to explain the electronic as
well as the optical properties of organic compounds [15]. During molecular interactions, the highest
occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) are the
main participants. The HOMO donates electrons and its energy corresponds to the ionization
potential (I.P.), whereas the LUMO accepts the electrons and its energy corresponds to the electron
affinity (E.A.).
FMO analysis of all products 4a–g was performed at the same level as used for optimization.
The resulting HOMO-LUMO surfaces are shown in Figure 1, and their corresponding energies along
with the energy gaps are listed in Table 2. The FMO analysis revealed that the isodensities are mainly
concentrated on thiophene and aromatic moieties. The HOMO-LUMO energy gap for 4b is found
19917

Molecules 2015, 20, 19914–19928
to be the highest and equal to 4.60 eV whereas the lowest band gap (3.99 eV) was observed for 4f.
The isodensity in the HOMO of 4b is mainly spread only on the thiophene and phenyl rings, which
reflects less conjugation in 4b. This observation indicates the HOMO-LUMO gap in 4b should display
the highest energy among all products studied, and indeed this was the case. The high energy gap in
4
b would render it more stable towards ionization (vide infra).
Table 2. HOMO and LUMO energies along with HOMO-LUMO energy gap of products 4a–g.
Entry
HOMO (a.u.)
LUMO (a.u.)
HOMO-LUMO (∆E/eV)
4
a
´0.24078
´0.26085
´0.24906
´0.23451
´0.23540
´0.22386
´0.24329
´0.07273
´0.09138
´0.08507
´0.07014
´0.06935
´0.07710
´0.07937
4.57
4.60
4.46
4.47
4.51
3.99
4.45
4
b
4
c
4
4
d
e
4
f
4
g
4
a (HOMO)
4a (LUMO)
4b (LUMO)
4b (HOMO)
4
c (HOMO)
4c (LUMO)
4d (LUMO)
4d (HOMO)
4
e (HOMO)
4e (LUMO)
4f (LUMO)
4g (LUMO)
4
f (HOMO)
4g (HOMO)
Figure 1. HOMO-LUMO surfaces of all products 4a–g.
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Molecules 2015, 20, 19914–19928
In 4a the is density on the HOMO is more or less spread over the same region as compared to 4b,
therefore its energy gap is comparable to that of 4b (i.e., of 4.57 eV). On the other hand, the HOMO
of 4f has the maximum density spread over the entire scaffold (including the CH substituent, which
3
results in the lowest energy gap (3.99 eV) and highest reactivity among all the compounds. The lowest
energy gap in 4f is expected due to the presence of planarity and the electron donating effect of the
methyl group. The extent of conjugation in the LUMO in all compounds is almost similar (Figure 1),
however, the intensities are slightly different.
2
.2.3. Molecular Electrostatic Potential (MEP)
One of the most interesting feature of quantum chemical investigations is to explain the
reactivity of compounds under investigation. In term of reactivity, electrostatic potential also plays
an important role in explaining reactivity. The reactivity of chemical systems can be explained by
predicting electrophilic as well as nucleophilic sites in target molecules [16]. Mathematically, MEP
can be expressed by using the following equation:
`
˘
ż
1
ÿ
ZA
ρ r
1
V prq “
´
dr
(1)
1
|
R ´ r|
A
|r ´ r|
ř
1
Summation ( ) runs over all nuclei, Z is charge of nucleus, located at distance RA and ρ(r )
A
is the electron density. MEP mapping using DFT methods can be useful in structural biology to
determine ligand-substrate interactions, drug receptor and in enzyme-substrate interactions [17].
During MEP mapping two regions red and blue appear, the preferred nucleophilic site is represented
by red color and the preferred electrophilic site is represented by blue color. The molecular
electrostatic potential of all products 4a–g was computed at the B3LYP/6-31G (d, p) level of DFT
and the surfaces are shown in Figure 2.
MEP analysis of all products 4a–g revealed that the negative potential is concentrated on the
oxygen of the sulfacetamide moiety (attached to the thiophene ring) and as a result this is the
preferred site for electrophilic attack as well as for cations, whereas a positive potential indicating
the site for nucleophilic attack is concentrated on the NH group of the sulfacetamide. The negative
and positive potential values of individual products are listed in Table 3.
Table 3. Values of ´ve and +ve potential of products 4a–g, computed at the DFT/B3LYP/6-31G
(d, p) level.
Entry
´ve Potential (a.u.)
+ve Potential (a.u.)
4
a
´0.07342
´0.07182
´0.06974
´0.07444
´0.07459
´0.07400
´0.07096
0.07342
0.07182
0.06974
0.07014
0.07459
0.07400
0.07096
4
4
b
c
4
4
d
e
4
f
4
g
From the results in Table 3, it is clear that the ´ve and +ve potential of all products are found
to be almost in the same range and no significant difference was observed. The smallest value
was observed for 4c, which ranged from ´0.06974 a.u. to 0.06974 a.u. (´ve sign is showing the
´
ve potential and vice versa), whereas the highest value was observed for 4e, (´0.07459 a.u. to
0
.07459 a.u.).
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Molecules 2015, 20, 19914–19928
4
a
c
4b
4d
4
4e
4f
4g
Figure 2. MEP Surfaces of all products 4a–g.
2
.2.4. Hyperpolarizability and Non-Linear Optical (NLO) Properties
Materials having high nonlinear optics (NLO) responses are very useful in optoelectronic
devices, and non-linear optics have great applications in information technology, and in other
industries [18]. NLO materials also have wide range applications for photonic communication
and digital memory devices, national defense and the pharmaceutical industry [19]. Compounds
having electron donor and electron acceptor groups along with a π-conjugated system can be
considered as strong candidates for such applications. In order to investigate the relation between
molecular structure and NLO properties, the first hyperpolarizibility value of all compounds 4a–g
was simulated at the B3LYP/6-31G (d, p) level of theory along with the additional keyword POLAR
and mathematically calculated using the following equation:
2
2
2 1/2
β tot “ rpβxxx ` βxyy ` βxzzq ` pβyyy ` βyzz ` βyxxq ` pβzzz ` βzxx ` βzyyq s
(2)
The value of the first hyperpolarazibility is determined in a.u. and then converted to esu using
´
33
the conversion factor 1 a.u. = 8.6393 ˆ 10
esu. The calculated first hyperpolarizibility parameters
of compounds 4a–g are given in Table 4. As reflected from the data, the first hyperpolarizibility values
show the same trend according to the electron donating and withdrawing capacity, and extended
´
30
π-conjugation pattern. Compound 4b has the lowest value of hyperpolarazibility (1.857 ˆ 10
esu),
because of the similar electronic nature at both termini. On the other hand 4f, having a CH group
3
on one side (electron donating) and a sulfonamide (electron withdrawing) on the other showed the
highest value (12.879 ˆ 10´ esu), which suggests that 4f has the potential to serve as a candidate
30
19920

Molecules 2015, 20, 19914–19928
for non-linear optical material. Furthermore, the first hyperpolarizability can also be correlated to
the HOMO-LUMO energy gap. Compound 4b (with the highest energy gap, 4.60 eV) has the lowest
hyper-polarizability value. On the other hand, the easy flow of electrons in 4f from one terminus of
the molecule to the other renders a higher hyperpolarizability value, and 4f also has lowest band gap
(HOMO-LUMO) being the most reactive among all the products as well.
Table 4. First hyperpolarizability parameters of 4a–g.
Entry
4a
4b
4c
4d
4e
4f
4g
βxxx
βxxy
βxyy
βyyy
βxxz
Bxyz
βyyz
βxzz
βyzz
βzzz
´546.18 118.57
1043.62 ´1159.69 ´804.94 1627.21 1301.99
´27.13
26.92
32.77
´37.90
6.16
66.68
53.51
´49.74
59.80
5.61
´16.19
´94.92
45.99
26.81
´18.56
0.29
56.93
22.73
´184.46 ´122.23
10.45
´31.44
11.45
23.43
´2.37
4.35
´60.06
´83.06
´5.87
1.38
´67.96
´47.42
13.17
44.77
´66.36
2.75
1.38
´9.85
33.85
´1.45
10.04
1.857
1.27
´10.85
´25.01
4.56
95.61
18.20
33.17
3.67
´19.52
109.00
25.42
41.49
8.690
58.63
´112.32 80.98
8.08
19.56
8.973
3.92
56.31
6.251
19.57
4.35
12.879
2.39
51.02
11.998
βtot ˆ 10´ (esu)
33
2
.3. Biological Activity
2
.3.1. Urease Inhibition Activity
Urease is an enzyme which converts urea to ammonium carbonate and is used as a diagnostic
tool to establish the presence of different pathogens in the urinary and gastrointestinal tract [20]. The
percentage activity values of urease enzyme of compounds 4a–d were measured at 50 µg/mL and
2
50 µg/mL (Table 5), whereas, for compounds 4e–g, the percentage activity values of urease enzyme
were measured at 15, 40 and 80 µg/mL, respectively (Table 6). Thiourea that showed IC50 values of
4
3 µg/mL and 23.3 µg/mL at various concentrations was used as a standard drug.
Table 5. Urease inhibition studies of 5-arylthiophene-2-sulfonylacetamides 4a–d.
Entry
Percentage Activity at 50 µg/mL
Percentage Activity at 250 µg/mL
IC50 µg/mL
4
a
67.56 ˘ 0.007
29.98 ˘ 0.034
54.4 ˘ 0.002
13.34 ˘ 0.007
60 ˘ 0.032
89 ˘ 0.01
56 ˘ 0.006
78 ˘ 0.003
54 ˘ 0.004
95 ˘ 0.09
38.4 ˘ 0.32
82.01 ˘ 0.79
42.5 ˘ 0.41
218 ˘ 1.98
43 ˘ 0.38
4
b
4
c
4
d
Standard
Table 6. Urease inhibition studies of 5-arylthiophene-2-sulfonylacetamides 4e–g.
Percentage Activity at
5 µg/mL
Percentage Activity at
Percentage Activity at
Entry
IC50 µg/mL
1
40 µg/mL
80 µg/mL
4
4
e
f
44.59 ˘ 0.14
42.44 ˘ 0.11
46.23 ˘ 0.11
47.1 ˘ 0.31
91.21 ˘ 0.81
92.12 ˘ 0.21
90.97 ˘ 0.18
65 ˘ 0.01
92.88 ˘ 0.14
94.66 ˘ 0.11
68 ˘ 0.02
17.9 ˘ 0.13
17.1 ˘ 0.15
23.3 ˘ 0.21
4
g
Standard
Urease inhibition activity of this newly synthesized 5-arylthiophene-2-sulfonylacetamide
compounds 4a–g was investigated to gain knowledge about their possible interaction with
the active site of the enzyme. Since Urease belongs to the family of hydrolases any
restrain in the activity of the enzyme would be expected to express in terms of reduced
19921

Molecules 2015, 20, 19914–19928
1
1
hydrolysis of its substrate [21]. Herein, we show that the compound 4f, N-((5 -methyl-[2,2 -
bithiophen]-5-yl)sulfonyl)acetamide, showed excellent urease inhibition activity at 40 µg/mL
and 80 µg/mL concentrations where the percentage inhibition values were found to be
9
2.12 ˘ 0.21 and 94.66 ˘ 0.11, respectively with an IC
value ~17.1 ˘ 0.15 µg/mL.
50
This was followed by compounds 4e, N-((5-(3,5-dimethylphenyl)thiophen-2-yl)sulfonyl)acetamide,
and 4g, N-((5-(4-chlorophenyl)thiophen-2-yl)sulfonyl)acetamide, that showed significant urease
inhibition with IC50 values of 17.9 + 0.13 and 23.3 + 0.21 µg/mL, respectively. Compound 4a,
N-((5-phenylthiophen-2-yl)sulfonyl)acetamide showed good urease inhibition at 50 µg/mL
and 250 µg/mL concentrations, where the percentage inhibition values were found to be
6
7.56 ˘ 0.007 and 89 ˘ 0.01, respectively, in addition to an IC
value ~38.4 µg/mL.
0
5
N-((5-(p-Tolyl)thiophen-2-yl)sulfonyl)acetamide (4d) showed a 13.34 ˘ 0.007 value of percentage
inhibition at 50 µg/mL concentration along with an IC50 value ~43 µg/mL. For the
compounds N-((5-(3,5-bis(trifluoromethyl)phenyl)thiophen-2-yl)sulfonyl)acetamide (4b) and N-((5-
(3,4-dichlorophenyl)thiophen-2-yl)sulfonyl)acetamide (4c) moderate urease inhibition activities
were observed, with percentage inhibition values ~56 ˘ 0.006 and 78.11 ˘ 0.003 at 250 µg/mL
concentration, along with IC50 values ~82.01 µg/mL and 42.5 µg/mL, respectively (Table 6),
suggesting that the electronic effects and presence of different functional groups on aromatic rings
and sulfacetamide moiety had a strong effect on the urease inhibitory action of these compounds.
Since, the electronic and steric factors have great influence on the biological activities [22], it was
surprising to see that the electron withdrawing and electron donating functional groups present on
the benzene ring exhibited low and high inhibitor action against urease enzyme [23]. Note worthily,
electron withdrawing groups decrease the metal chelating activity and vice versa, therefore, the
removal of Ni2 ions through chelation may result in the inactivation of the enzyme. It is further
concluded that the urease inhibitory activity might be affected by the presence of the electronic effects
of functional groups and the position of functional groups in the 4a–g series of compounds.
+
2
.3.2. Antibacterial Activity
Kulsoom et al. reported that sulfacetamides are effective against different Escherichia coli and
Staphylococcus aureus strains and sulfacetamide suspension can be used for the treatment of eye
infections caused by Staphylococcus aureus [24]. Therefore, we examined all newly synthesized
compounds 4a–g for their antibacterial activity. A general antibacterial sensitivity test (inhibition
zone, mm) was performed on six test organisms (Bacillus subtiles, Escherichia coli, Staphylococcus aureus,
Shigella dysenteriae, Salmonella typhae, Pseudomonas aeruginosa) by using agar diffusion
according to the reported methods [25] for all the new 5-bromothiophene-2-sulfonylacetamide
derivatives and the clinical standard ampicillin. The antibacterial activity of all new
5
-arylthiophene-2-sulfonylacetamide (sulfacetamide) derivatives 4a–g was authenticated via
in vitro screening against six strains and was calculated from zones of inhibition (ZOI).
The obtained antibacterial results at different concentrations (100, 300 and 1000 µg) are
summarized in Tables 7–9 respectively. N-((5-Phenylthiophen-2-yl)sulfonyl)acetamide (4a)
showed the highest activity against Shigella dysenteriae at 100 µg and 1000 µg concentration
with percentage activity values ~55.7 ˘ 0.016 and 80 ˘ 0.00, respectively (Tables 7
and 9). Noticeably, N-((5-(3,5-bis(trifluoromethyl)-phenyl)thiophen-2-yl)sulfonyl)acetamide (4b)
produced the highest activity against Escherichia coli at 100 µg and 1000 µg concentrations,
with percentage activity values ~20 ˘ 0.01 and 62 ˘ 0.004, respectively. At 300 µg
concentration, compound 4b also showed the highest activity against Pseudomonas aeruginosa
with a percentage activity value ~44.81 ˘ 0.009 as shown in Table 8. Note worthily,
N-((5-(3,4-dichlorophenyl)thiophen-2-yl)sulfonyl)acetamide (4c) exhibited a high percentage of
activity against a Salmonella typhae stain at 1000 µg with a value ~64 ˘ 0.0012 (Table 9). It
was found that the compound N-((5-(4-chlorophenyl)thiophen-2-yl)sulfonyl)acetamide (4g)
exhibited the highest activity against Bacillus subtiles with percentage activity value ~78 ˘ 0.007
19922

Molecules 2015, 20, 19914–19928
at 1000 µg concentration. N-((5-(p-tolyl)thiophen-2-yl)sulfonyl)acetamide (4d) also showed
a promising percentage of antibacterial activity against a Shigella dysenteriae strain, with
a value ~52.36 ˘ 0.002 at 300 µg. The present study also examined the response of
N-((5-(3,5-dimethylphenyl)thiophen-2-yl)sulfonyl)acetamide (4e) against Pseudomonas aeruginosa
at 1000 µg concentration with an observed percentage activity value ~67
N-((5 -methyl-[2,2 -bithiophen]-5-yl)sulfonyl)acetamide (4f) also showed noticeable bacterial
inhibition, as can be seen from the values outlined in Table 7.
˘
0.04.
1
1
Taken together, it is very significant to note that all newly synthesized 5-arylthiophene-
2
1
-sulfonylacetamide derivatives of gave better percentage antibacterial activity results ranging from
00 µg to 1000 µg concentrations. In addition, all compounds showed a concentration dependent
inhibitory effect in the in vitro microbial growth assay [26]. It is worth considering that the
antibacterial activity in all these compounds may depend on the nature of the substituent (R) group,
even though all the compounds showed significant antibacterial inhibition. It was concluded that
sulfacetamide derivatives with electron donating and electron withdrawing functional groups may
lead to a much stronger and more effective antibacterial activity.
Table 7. Antibacterial activities (100 µg) of 5-arylthiophene-2-sulfonylacetamide 4a–g.
%
Activity at 100 µg
Gram Positive
Bacteria
Gram Negative
Bacteria
Gram Positive
Bacteria
Gram Negative
Bacteria
Gram Negative
Bacteria
Salmonella
typhae
Gram Negative
Bacteria
Pseudomonas
aeruginosa
Entry
Staphylococcus
aureus
Shigella
dysenteriae
Bacillus subtiles
Escherichia coli
4
a
17 ˘ 0.0007
17 ˘ 0.005
14.1 ˘ 0.002
20 ˘ 0.007
15 ˘ 0.035
19 ˘ 0.007
22 ˘ 0.019
13 ˘ 0.007
20 ˘ 0.01
16 ˘ 0.00
20 ˘ 0.007
20 ˘ 0.035
12 ˘ 0.001
12. ˘ 0.01
82 ˘ 0.2
19.03 ˘ 0.0
17.7 ˘ 0.007
13.89 ˘ 0.002
18.35 ˘ 0.0007
17.96 ˘ 0.0007
19.86 ˘ 0.001
20.17 ˘ 0.02
65 ˘ 0.22
55.7 ˘ 0.016
38.59 ˘ 0.0007
15.59 ˘ 0.004
19.93 ˘ 0.038
26.93 ˘ 0.038
38.33 ˘ 0.0007
31.1 ˘ 0.009
60 ˘ 0.18
39.31 ˘ 0.008
36.57 ˘ 0.005
34.95 ˘ 0.012
33.26 ˘ 0.002
33.70 ˘ 0.009
48.55 ˘ 0.014
32.51 ˘ 0.006
86 ˘ 0.5
39.32 ˘ 0.004
32.0 ˘ 0.006
27.2 ˘ 0.004
24.1 ˘ 0.004
25.05 ˘ 0.005
35.05 ˘ 0.004
32.06 ˘ 0.004
55 ˘ 0.12
4
b
4
c
4
d
4
e
f
4
4
g
Ampicillin 60.2 ˘ 0.32
Table 8. Antibacterial activities (300 µg) of 5-arylthiophene-2-sulfonylacetamide 4a–g.
%
Activity at 300 µg
Gram Positive
Bacteria
Gram Negative
Bacteria
Gram Positive
Bacteria
Gram Negative
Bacteria
Gram Negative
Bacteria
Salmonella
typhae
Gram Negative
Bacteria
Pseudomonas
aeruginosa
Entry
Staphylococcus
aureus
Shigella
dysenteriae
Bacillus subtiles
Escherichia coli
4
a
34 ˘ 0.06
28.2 ˘ 0.01
26.3 ˘ 0.001
40.0 ˘ 0.000
40.01 ˘ 0.001
24.5 ˘ 0.00
37 ˘ 0.144
85 ˘ 0.51
29 ˘ 0.06
30 ˘ 0.02
27 ˘ 0.006
34 ˘ 0.05
40 ˘ 0.01
25 ˘ 0.00
35 ˘ 0.144
88 ˘ 0.6
32.22 ˘ 0.002
32.16 ˘ 0.0007
22.50 ˘ 0.003
27.35 ˘ 0.0003
27.80 ˘ 0.0004
28.74 ˘ 0.0007
29.57 ˘ 0.0007
78 ˘ 0.45
51.78 ˘ 0.001
51.7 ˘ 0.000
50.17 ˘ 0.001
52.36 ˘ 0.002
45.96 ˘ 0.017
49.30 ˘ 0.023
52.94 ˘ 0.001
76.2 ˘ 0.29
29.06 ˘ 0.016
36.12 ˘ 0.006
31.2 ˘ 0.0091
34.22 ˘ 0.0007
28.8 ˘ 0.021
33.58 ˘ 0.007
40.2 ˘ 0.016
89 ˘ 0.18
38.53 ˘ 0.010
44.81 ˘ 0.009
40.64 ˘ 0.03
40.05 ˘ 0.038
40.74 ˘ 0.06
41.86 ˘ 0.043
38.4 ˘ 0.003
72 ˘ 0.61
4
b
4
c
4
d
4
e
f
4
4
g
Ampicillin
Table 9. Antibacterial activities (1000 µg) of 5-arylthiophene-2-sulfonylacetamide 4a–g.
%
Activity at 1000 µg
Gram Positive
Bacteria
Gram Negative
Bacteria
Gram Positive
Bacteria
Gram Negative
Bacteria
Gram Negative
Bacteria
Salmonella
typhae
Gram Negative
Bacteria
Pseudomonas
aeruginosa
Entry
Staphylococcus
aureus
Shigella
dysenteriae
Bacillus subtiles
Escherichia coli
4
a
60 ˘ 0.004
32 ˘ 0.004
31 ˘ 0.0003
54 ˘ 0.009
75 ˘ 0.01
64 ˘ 0.004
62 ˘ 0.004
44 ˘ 0.001
59 ˘ 0.01
74 ˘ 0.01
54 ˘ 0.00
71 ˘ 0.007
95.9 ˘ 0.21
64 ˘ 0.004
59 ˘ 0.0021
58 ˘ 0.005
59 ˘ 0.00
80 ˘ 0.00
73 ˘ 0.0034
74 ˘ 0.015
75 ˘ 0.023
65 ˘ 0.004
67 ˘ 0.045
75 ˘ 0.02
55 ˘ 0.009
56 ˘ 0.007
64 ˘ 0.0012
62 ˘ 0.003
58 ˘ 0.0054
65 ˘ 0.001
68 ˘ 0.0004
98.9 ˘ 0.26
46 ˘ 0.12
45 ˘ 0.0021
48 ˘ 0.045
65 ˘ 0.03
67 ˘ 0.04
64 ˘ 0.0012
43 ˘ 0.5
4
b
4
c
4
d
4
e
f
55.5 ˘ 0.0012
56 ˘ 0.004
61 ˘ 0.006
92.3 ˘ 0.32
4
4
34 ˘ 0.0021
78 ˘ 0.007
92 ˘ 0.55
g
Ampicillin
91.6 ˘ 0.61
92 ˘ 0.44
19923

Molecules 2015, 20, 19914–19928
3
. Experimental Section
3
.1. General Information
All reagents and chemicals were purchased from Sigma Aldrich (St. Louis, MO, USA) and
Alfa Aesar (Heysham, Lancashire, UK). A B-540 melting point apparatus (Büchi Labortechnik AG,
1
13
Switzerland) was used to record the melting points. H-NMR and C-NMR spectrum was measured
in CDCl and CD OD at 400/100 MHz on an Aspect AM-400 instrument (Bruker, Billerica, MI, USA).
3
3
Chemical shifts are reported in δ (ppm) units, while the coupling constant values were reported in
Hz. A Jeol JMS 600 mass spectrometers with a data system (Akishima, Tokyo, Japan) was used to
record EI-MS spectrum. Column chromatography was used to purify compounds, using silica gel
(
230–400 mesh size and 70–230 mesh size). Silica gel 60 PF254 TLC plates (Merck, Germany) were
used to monitor all reactions. The newly synthesized compounds were detected/visualized by UV
254–365 nm).
(
3
.2. Synthesis of 5-Bromothiophene-2-sulphonamide (2)
For the synthesis of 5-bromothiophene-2-sulfonamide from 2-bromothiophene (1), freshly
distilled chlorosulfonic acid solution was added drop wise under continuous stirring to a solution
˝
of compound 1 (12 mmol) in CCl (6 mL), cooled to ´30 C. Stirring was done for another 30 min at
4
˝
´
25 C, and the mixture was then kept at room temperature for another 30 min. The organic layer was
separated and solvent was removed under reduced pressure. Next, 25% ammonia solution (50 mL)
was mixed with the residue, stirred for 3 h and neutralized with 10% HCl. The desired product was
filtered, dried and compared with previously reported 5-bromothiophene-2-sulphonamide [12].
3
.3. Synthesis of 5-Bromothiophene-2-sulfonylacetamide (Sulfacetamide) (3)
To an acetonitrile solution (5 mL) containing 5-bromothiophene-2-sulfonamide (2, 0.002 mmol)
and acetic anhydride (0.0031 mmol), a few drops of concentrated sulfuric acid were added and the
˝
mixture was stirred for 40 min at 60 C under a nitrogen atmosphere. Later, distilled water (about
5–20 mL) was added to this solution and stirred for 1 h at room temperature. The solution was then
1
filtered and the precipitates were collected, washed and dried. Further purification and identification
was done by flash chromatography and various spectroscopic techniques, respectively [1]. M.P.
˝
18–120 C; H-NMR (CDCl ): δ 8.44 (s, 1H, NH), 7.62 (d, J = 4.4, 1H-thiophene), 7.09 ( d, J = 4,
3
1
1
1
13
H-thiophene), 2.12 (s, 3H, CH3), C-NMR (CDCl + CD OD): δ = 23.6, 122.2, 130.2, 135.4, 174.2;
3
3
+
+
+
EI-MS (m/z, + ionmode): 284.00 [M + H] ; 282.00; [M ´ SO ] = 219; [ M ´ NH and acetyl fragment]
2
+
=
226; [M ´ SO and acetyl fragment] = 178. Anal. Calcd. For C H NBrO S : C, 25.36; H, 2.13; N,
2
6
6
3 2
4
.93; Found: C, 25.46; H, 2.52; N, 5.12.
3
.4. General Procedure for the Synthesis of 5-Arylthiophene-2-sulfonylacetamides 4a–g
To a 1,4-dioxane (3 mL) solution of 5-bromothiophene-2-sulfonylacetamide (3, 0.704 mmol)
5
mol % Pd(PPh ) was added and the resulting mixture stirred for 30 min at room temperature under
3 4
a nitrogen atmosphere. Next, arylboronic acids and arylboronic esters (0.774 mmol), and potassium
phosphate (1.409 mmol) were added along with water (1.5 mL) under a nitrogen atmosphere. The
˝
˝
solution was stirred at 95 C for 30 h and later cooled to 20 C. Later on H O was added and the
2
reaction mixture was extracted with ethyl acetate to obtain an organic layer that was filtered and
dried by the addition of MgSO . The solvent was removed under reduced pressure. The residue
4
was purified by column chromatography using ethyl acetate and n-hexane (1:1) to obtain the desired
products which were characterized by spectroscopic techniques.
˝
1
N-((5-Phenylthiophen-2-yl)sulfonyl)acetamide (4a). M.P. 158–160 C; H-NMR (CDCl ): δ 8.77 (s, 1H,
3
NH), 7.61–7.00 (m, 5H-Ar, 2H-thiophene), 2.10 (s, 3H, CH3). 13C-NMR (CDCl + CD OD): δ = 23.6,
3
3
19924

Molecules 2015, 20, 19914–19928
1
2
27.7, 128.2, 129.1, 129.9, 130.2, 132.1, 135.3, 139.7, 174.1; EI-MS (m/z, + ionmode): 281.00 [M + H]+;
82.00. Anal. Calcd. For C H NO S : C, 51.23; H, 3.94; N, 4.98. Found: C, 51.28; H, 3.96; N, 4.98.
12
11
3 2
N-((5-(3,5-Bis(trifluoromethyl)phenyl)thiophen-2-yl)sulfonyl)acetamide (4b). M.P. 168 C; 1H-NMR
(
˝
13
CDCl ): δ 8.77 (s, 1H, NH), 7.9–7.10 (m, 3H-Ar, 2H-thiophene), 2.12 (s, 3H, CH ). C-NMR (CDCl +
3
3
3
CD OD): 24.0, 123.3, 125.1, 127.3, 129.2, 130.4, 133.2, 134.6, 136.4, 139.8, 174.3; EI-MS (m/z, ´ionmode):
3
+
4
16.08 [M ´ H] . Anal. Calcd. For C1 H F NO S : C, 40.29; H, 2.17; N, 3.36. Found: C, 40.46; H, 2.52;
4
9
6
3 2
N, 3.42.
˝
1
N-((5-(3,4-Dichlorophenyl)thiophen-2-yl)sulfonyl)acetamide (4c). M.P. 148–150 C; H-NMR (CDCl ): δ
8
3
13
.77 (s, 1H, NH), 7.30–7.85 (m, 4H-Ar, 2H-thiophene), 2.10 (s, 3H, CH3). C-NMR (CDCl + CD OD):
3 3
δ = 23.8, 123.8, 128.1, 129.2, 130.1, 131.4, 132.0, 133.4, 133.2, 139.0, 173.8; EI-MS (m/z, +ionmode):
+
+
+
3
50.00 [M + H] ; 351.17; [M – O] = 336.50; [M ´ NH and acetyl fragment and SO ] = 273. Anal.
2
Calcd. For C H Cl NO S : C, 41.15; H, 2.59; N, 4.00. Found: C, 41.59; H, 2.60; N, 4.02.
12
9
2
3 2
˝
1
N-((5-(p-Tolyl)thiophen-2-yl)sulfonyl)acetamide (4d). M.P. 161–163 C; H-NMR (CDCl ): δ 8.77 (s,
3
13
1
H, NH), 7.62–7.09 (m, 4H-Ar, 2H-thiophene), 2.09 (s, 3H, CH ), 2.34 (s, 3H, CH ).
C-NMR
3
3
(
(
CDCl + CD OD): δ = 23.8, 24.6, 127.8, 127.2, 128.6, 131.0, 132.2, 134.4, 134.7, 139.4, 173.4; EI-MS
3
3
+
m/z, ´ionmode): 295.00 [M ´ H] ; 294.17. Anal. Calcd. For C H NO S : C, 52.86; H, 4.44; N, 4.74.
13
13
3 2
Found: C, 52.88; H, 4.46; N, 4.76.
˝
1
N-((5-(3,5-Dimethylphenyl)thiophen-2-yl)sulfonyl)acetamide (4e). M.P. 148–149 C; H-NMR (CDCl ): δ
8
3
13
.77 (s, 1H-NH), 7.65–6.97 (m, 3H-Ar, 2H-thiophene), 2.10 (s, 3H, CH ), 2.37 (s, 3H, 2CH ). C-NMR
3 3
(
+
CDCl + CD OD): δ = 22.1, 23.4, 127.0, 127.9, 129.9, 131.0, 131.6, 134.2, 139.0, 139.3, 173.2; EI-MS (m/z,
3 3
+
ionmode): 309.40.00 [M ´ H] ; 308.25. Anal. Calcd. For C H NO S : C, 54.35; H, 4.89; N, 4.53.
14
15
3 2
Found: C, 54.36; H, 4.52; N, 4.54.
1
1
˝
1
N-((5 -Methyl-[2,2 -bithiophen]-5-yl)sulfonyl)acetamide (4f). M.P. 167–168.4 C; H-NMR (CDCl ): δ 8.77
3
(
s, 1H, NH), 7.71–7.09 (m, 3H-thiophene), 7.0 (d, J = 4.2, 1H-thiophene), 2.09 (s, 3H, CH ), 2.40 (s, 3H,
3
13
CH ). C-NMR (CDCl + CD OD) :δ = 16.1, 23.6, 125.6, 128.0, 128.4, 129.2, 133.3, 137.6, 137.2, 139.3,
1
3
3
3
+
73.9; EI-MS (m/z, +ionmode): 301.00 [M + H] ; 302.04. Anal. Calcd. For C H NO S : C, 43.83; H,
11 11 3 3
3
.68; N, 4.65. Found: C, 43.88; H, 3.68; N, 4.66.
˝
1
N-((5-(4-Chlorophenyl)thiophen-2-yl)sulfonyl)acetamide (4g). M.P. 167–170 C; H-NMR (CDCl ): δ 8.70
3
13
(
s, 1H, NH), 7.75–7.08 (m, 4H-Ar, 2H-thiophene), 2.09 (s, 3H, CH3). C-NMR (CDCl + CD OD):
3 3
δ = 22.7, 128.8, 129.0, 129.9, 131.0, 132.2, 134.4, 134.7, 139.4, 173.4; EI-MS (m/z, +ionmode): 315.00
+
[
M + H] ; 316.10. Anal. Calcd. For C H ClNO S : C, 45.64; H, 3.19; N, 4.44. Found: C, 45.66; H,
12
10
3 2
3
.22; N, 4.48.
3
.5. Computational Methods
Computational simulations of all products 4a–g were performed using the Gaussian 09 software
at density functional theory (DFT) level, as instituted in [27]. The visualization of the results and
graphics was achieved using Gauss View 05 [28]. Energy minima optimization was carried out using
the DFT/B3LYP/6-31G (d, p) basis set. Frequency simulations were performed at the same level, to
confirm the optimized geometries as true energy minima (no imaginary frequency was observed).
Furthermore optimized geometries were used for frontier molecular orbital (FMO) analysis, and
molecular electrostatic potential (MEP) mapping. Nonlinear optics properties were computed at the
same level of theory as used for optimization and just with the additional keyword POLAR.
3
.6. Urease Inhibition Activity
Jack bean urease enzyme (25 µL) was added in buffer solution (55 µL) containing 100 mM urea
to prepare the stock solution. This mixture was then incubated with 5 µL (0.5 mM concentration)
˝
of the newly synthesized compounds for 15 min at 30 C in 96-well plates. Anti-urease activity was
19925

Molecules 2015, 20, 19914–19928
resolved by knowing the production of ammonia using the indophenol method [29]. Concisely, in
each well, phenol reagent (45 µL, 0.005% w/v sodium nitroprusside and 1% w/v phenol) was added
in addition to the alkali reagent (70 µL, NaOH 0.5% w/v and 0.1% NaOCl). After 50 min, the increase
in absorbance was measured at 630 nm using a micro plate reader. All reactions were carried out in
triplicate to obtained 200 µL final volume. The Softmax pro software was used to obtain the results
as change in absorbance per minute. All assays were carried out at a specific pH of 6.8. The following
formula was used to calculate the % inhibition:
100 ´ pOD test well{OD controlq ˆ 100
(3)
Thiourea was used as standard inhibitor of urease [20]. The EZ-fit kinetic data base was used
to determine IC50 values [30]. In the case of colored compounds, sample blanks were also prepared.
Absorbance of sample blanks was subtracted from the absorbance of samples to get the corrected
absorbance of the samples. Corrected absorbance of sample was used to calculate % age inhibition.
3
.7. Antibacterial Activity Assay
Determination of Minimum Inhibitory Concentrations
All the sulfonamide derivatives were dissolved at 250 µg/mL concentration in dimethyl
sulphoxide. Nutrient ager was composed of NaCl (10 g), bactotryptone (10 g) and (5 g) yeast extract
with a final pH value of 7.4. After that, the mixture was left for 18 h to grow the six bacteria and
˝
after 18 h at 37 C, nutrient broth was diluted in sterile broth. To achieve a final bacterial count
6
of 1 ˆ 10 cell/mL, 1 mL from each dilution was added to 100 mL of cooled and sterilized nutrient
˝
agar media. These plates were kept at room temperature and dried at 37 C for 20 h. Whatman
No. 41 paper was used as paper discs for assays. Discs were soaked in test solutions of different
concentrations and placed at regular intervals of 6–7 cm on inoculated agar media; there should not
be any extra solution on the discs so care was taken when discs were soaked in solution. These
˝
plates were incubated at 37 C, and antibacterial activity was determined by measuring the zone of
inhibition in mm. Growth inhibition was calculated by the method of difference to positive control.
4
. Conclusions
In the present study, we have reported the synthesis of 5-aryl thiophenes sulphonylacetamide
sulfacetamide) derivatives through Pd[0] catalyzed Suzuki cross coupling reactions of
-bromothiophene acylsulfonamide with various aryl boronic acids/esters under mild conditions.
(
5
1
13
A wide range of spectroscopic techniques, including H-NMR, C-NMR and mass spectroscopy
were applied to elucidate the structure of the synthesized compounds. DFT investigations were
performed to gain insight into the structure activity relationships. FMO analysis revealed that 4b
has the highest HOMO-LUMO energy gap (4.60 eV) and therefore is the least reactive among all the
prepared derivatives, while as 4f has lowest energy gap (3.99 eV) and was the most reactive. MEP
mapping indicated the sites for nucleophilic as well as electrophilic attack over the entire geometry.
´
30
First hyperpolarizability analysis revealed that 4f has the highest value (12.879 ˆ 10
esu) among
all products, therefore it can act as a potential candidate for nonlinear optics applications. In addition,
the synthesized compounds were explored as anti-urease and antibacterial molecules. This studied
offered a preliminary structure-activity study of 5-aryl thiophenes bearing sulphonylacetamide
moieties that have a great scope and potential use in pharmaceutical chemistry.
Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/
2
0/11/19661/s1.
Acknowledgments: The data present here is part of the Ph.D thesis of Mnaza Noreen. The authors gratefully
acknowledge the financial support by the Higher Education Commission (HEC), Pakistan through a scholarship
(PIN NO. 106-2102-Ps6-070) to Mnaza Noreen.
19926

Molecules 2015, 20, 19914–19928
Author Contributions: M.N., N.R., Y.G., M.Z., T.M., K.A., F.-H.N., A.Y and M.H. made a significant contribution
to experiment design, acquisition of data, analysis and drafting of the manuscript. V.F. has made a substantial
contribution to interpretation of data, drafting and carefully Revising the manuscript for intellectual content. All
authors read and approved the final manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 4a–g are available from the authors.
2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open
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Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
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