Synthesis, structural characterization and in vivo anti-diabetic evaluation of some new sulfonylurea derivatives in normal and silicate coated nanoparticle forms as anti-hyperglycemic agents

Article abstract of DOI:10.1016/j.bioorg.2019.103290

Series of new sulfonylurea derivatives (gliclazide analogues) was synthesized and characterized. Thus, p-tolylsulfonylisocyanate was left to react with different amino derivatives under mild conditions to afford the desired sulfonylurea derivatives 1–5. T

Full text of DOI:10.1016/j.bioorg.2019.103290

BioorganicChemistry92(2019)103290
Contents lists available at ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
Synthesis, structural characterization and in vivo anti-diabetic evaluation of
some new sulfonylurea derivatives in normal and silicate coated
nanoparticle forms as anti-hyperglycemic agents
⁎
Farid M. Sroora, , Samir Y. Abbasa, Wahid M. Basyounia, Khairy A.M. El-Bayoukia,
Mohamed F. El-Mansya, Hanan F. Alyb, Sanaa A. Alib, Azza F. Arafab, Ahmed A. Harounc
a Organometallic and Organometalloid Chemistry Department, National Research Centre, 12622 Cairo, Egypt
b Department of Therapeutic Chemistry, National Research Centre, Cairo, Egypt
c Chemical Industries Research Division, National Research Centre, Cairo, Egypt
A R T I C L E I N F O
A B S T R A C T
Keywords:
Series of new sulfonylurea derivatives (gliclazide analogues) was synthesized and characterized. Thus, p-to-
lylsulfonylisocyanate was left to react with different amino derivatives under mild conditions to afford the
desired sulfonylurea derivatives 1–5. The molecular structure of the compound N-(2,6-
Dichlorophenylcarbamoyl)-4-methylbenzenesulfonamide, 1c has been elucidated by single crystal X-ray dif-
fraction. Anti-diabetic properties of the synthesized compounds relative to anti-diabetic drug (gliclazidem
MR60) were carried out, where most of the tested compounds showed significant activity for reducing the blood
glucose level. The results revealed that compounds 1c and 5 showed better anti-diabetic activities compared
with gliclazide. Activity of the most potent derivatives of sulfonylurea compounds namely 1c and 5 were in-
creased using coated nanostructure tetraethyl orthosilicate (TEOS) as a modified release (MR) agent. The effect
of the prepared sulfonylurea compounds against the diabetic condition was investigated using specific selected
biomarkers as of liver enzyme activities as transaminases (AST, ALT) and alkaline phosphatase (ALP), lipids
profiles; total cholesterol (TC), triacylglycerols (TG) and total lipid (TL). The antioxidants, oxidative stress
biomarkers and histological examination were also examined and discussed.
Diabetes mellitus
Sulfonylurea
Gliclazide
Diamicron
Anti-diabetic drug
1. Introduction
Sulfonylurea drugs are one of the first widely used oral anti-diabetic
drugs and in the medical community sulfonylurea drugs were used as
Diabetes mellitus is metabolic disease where human have high
blood sugar. This increase in blood sugar level is either due to presence
of insufficient insulin, or because the cells do not respond to the pro-
duced insulin [1]. The high blood sugar produces symptoms such as
frequent urination, increased thirst and increased hunger. Diabetic
human without treated suffer from many acute and chronic complica-
tions. Some of acute complications are diabetic ketoacidosis and non-
ketotic hyperosmolar coma. Some of chronic complications are chronic
renal failure, cardiovascular disease, and diabetic retinal damage. So,
treatment of diabetes is very important.
complementary to metformin. They prevent the long-term complica-
tions of diabetes, which caused by changes in the blood vessels.
Sulfonylurea drug (such as gliclazide) help to stimulate the pancreas to
secrete insulin. Gliclazide is an oral hypoglycemic drug and classified as
a first and second-generation sulfonylurea [2,3]. Gliclazide protect
human pancreatic β-cells from hyperglycemia-induced apoptosis [4]
and prevents accumulation of fat in arteries in type 2 diabetes [5].
Accordingly, and in a connection with our previous works on or-
ganic and organometallic compounds in conjunction to our interest in
preparation of bioactive molecule [6–13], the present study is directed
to prepare derivatives of some new sulfonylurea compounds as glicla-
zide analogues that may be useful for treatment of diabetes.
Many useful drugs have been developed and they are sometime
appropriate to avoid troubles caused by sensitivity to insulin.
⁎ Corresponding author.
E-mail addresses: faridsroor@gmx.de, fm.sroor@nrc.sci.eg (F.M. Sroor).
https://doi.org/10.1016/j.bioorg.2019.103290
Received 10 February 2019; Received in revised form 30 July 2019; Accepted 16 September 2019
Availableonline18September2019
0045-2068/©2019ElsevierInc.Allrightsreserved.

F.M. Sroor, et al.
BioorganicChemistry92(2019)103290
Scheme 1. Synthesis of sulfonylurea derivatives. Reagents: (a) aniline derivatives, (b) 4-aminoantipyrine, (c) 1-adamantylamine, (d) 2-(1H-indol-3-yl) acetohy-
drazide, (e) pyrrolidine.
respectively, and the distances of S1eN1 and S1eC5 are 1.650 (2) Å
and 1.754 (2) Å, respectively. The N1eC6, C6eN2 and C6eO1 bond
lengths are 1.393 (3) Å, 1.340 (3) Å and 1.227 (3) Å, respectively. The
bon angles of the S1eN1eC6, N1eC6eN2, N1eS1eC5 and C6eN2eC7
are 129.72(17)°, 117.7(2)°, 105.64(11)° and 121.5(2)°, respectively. On
the other hand, the bond angles of O3eS1eC5 and O2eS1eC5 have the
same value 108.31(12)° and 108.80(12)°, respectively. In the same
manner, the bond angles of N1eS1eO3 and N1eS1eC5 have the same
value 105.34(11)° and 105.64(11)°, respectively. The torsion angles of
the plans S1N1C6N2 and C5S1N1C6 are 11.54° and 85.70°, respec-
tively. Therefore the geometry sphere around the sulfer ion could il-
lustrate as pseudo-tetrahedral. These values are well comparable to
those found in sulfamethoxazole [14] as depicted in Fig. 1.
2. Results and discussion
2.1. Chemistry
p-Tolylsulfonylisocyanate was used as a precursor for the synthesis
of different types of sulfonylurea derivatives via nucleophilic addition
reaction under mild conditions. Different substituents on phenyl moiety
were applied for discussing their effect on the anti-diabetic activity.
Thus, when p-tolylsulfonylisocyanate was left to react with mono-, di-,
and tri-substitued anilines, the corresponding sulfonylurea derivatives
1a-g were afforded in good yields (Scheme 1). Also, upon reacting p-
tolylsulfonylisocyanate with 4-amino-antipyrine, the sulfonylurea de-
rivative bearing a pyrazole moiety 2 was obtained. To obtain another
sulfonylurea derivative, p-tolylsulfonylisocyanate was left to react with
1-adamantylamine to afford sulfonylurea derivative 3. Also, upon re-
acting p-tolylsulfonylisocyanate with 2-(1H-indol-3-yl)acetohydrazide
gave and pyrrolidine, the corresponding sulfonylurea derivative 4 and 5
were obtained, respectively.
2.2. Preparation of silicate coated particles of 1c and 5 by TEOS
Although, some of these compounds are appeared very useful in
their actual prepared form, we need to determine their effects in na-
noscale in a trail to reduce the effective dose, prevent side effects,
augments their effects without any hazards for the dose and allow the
compounds to penetrate arteries and interact with beta cells receptors
through their nanoforms. Compound 1c exhibited particle size around
1204 nm, while after coating with tetraethyl orthosilicate (TEOS) via
sol-gel technique, it was 427 nm. On the other hand, compound 5 ex-
hibited particles size around 256 nm, after coating with tetraethyl or-
thosilicate (TEOS) it becomes about 115 nm (Table 1). Therefore, we
can conclude that the prepared silicate coated particles showed stable
particles with particle size in nanoscale. The compounds of silicate
coated via the technique of sol-gel led to enhancement of their effect,
through their easily penetrate to pancreas with the completely dose to
Structures of the synthesized sulfonylurea derivatives were con-
firmed by careful studying of their infrared IR, NMR as well as ele-
mental analyses. IR spectrum of products 1a-g revealed the NH peaks in
the regions 3433–3269 and 3283–3198 cm−1
, carbonyl peaks at
1698–1671 cm−1 region and SO2 at 1353–1344 and 1197–1149 cm−1
regions. 1H NMR spectra of all the obtained products supported these
assignments and added a strong evidence for these interpretations. 1H
NMR spectrum of compound 5, as representative example, was char-
acterized by the presence of two signals at: δ = 1.77 and 3.25 ppm
corresponding for pyrrolidine protons. A single signal at 2.39 ppm was
observed for the methyl protons. Beside the latter three aliphatic sig-
nals, the 1H NMR spectrum of compound 5 exhibited two douplet sig-
nals for AB aromatic protons at: 7.38 and 7.82 ppm with two proton
integral value which are assigned to protons at C-2,6 and C-3,5 carbons
of p-tolyl moiety. The broad exchangeable single at 10.41 ppm is as-
signed for the imine proton. The 13C NMR spectra of all the obtained
products supported these assignments and added a strong evidence for
these interpretations. 13C NMR spectrum of compound 5, as re-
presentative example, showed three signals in the aliphatic region. The
signals at 21.4, 25.2 and 46.3 ppm are due to pyrrolidine and methyl
carbons. The signals resonated at: 128.0 and 129.5 ppm are assigned to
4CH carbons, while the signals resonated at 138.6 and 143.6 ppm are
assigned to 2C carbons. The signals resonated in the deshielded region
at 150.9 ppm is assigned to C]O carbon.
The sufonylurea derivative 1c crystallizes from ethylacetate in the
monoclinic space group P 1 21/n 1 with four molecules in the unit cell.
The bond lengths of S1eO2 and S1eO3 are 1.430 (2) Å and 1.423 (3) Å,
Fig. 1. X-ray crystal structure of N-(2,6-Dichlorophenylcarbamoyl)-4-methyl-
benzene-sulfonamide, 1c.
2

F.M. Sroor, et al.
BioorganicChemistry92(2019)103290
Table 1
200
150
100
50
Particle size distribution analysis using DLS technique.
Sample code
Particle size (d·nm)
PDI
1c
1204.00
427.00
256.00
115.00
70.00*
30.40
6.60*
0.575
1.00
1c coated with TEOS
5
0.329
1.00
5 coated with TEOS
10.60
Statistical analysis is carried out using paired T-test computer program, where *
is highly significant at P ≤ 0.0001.
0
stimulate insulin secretion. Also, these formulated nanoparticles may be
interact with the receptors of the remaining β-cells of pancreas and
protect them from oxidative -induced apoptosis [4]. Furthermore, the
nano-compounds can be transfuse and succeed in forcing a way into
fine arteries, prevent accumulation of fat diabetes type 2 [5]. The ob-
tained data was confirmed by SEM-micrographs for the compounds 1c
and 5 in comparison with the coated ones. SEM images of compound 1c
showed needle-like shape particles, while after coating; it was observed
stable spherical-like shape structure. On the other hand, compound 5
showed rough surface with rigid particles, while after coating with
TEOS, it was observed soft brittle particles. The aforementioned results
proved that silicate coated compounds via sol-gel technique could be
successful prepared with different morphologies that led to enhance-
ment of their different applications.
Fig. 2. Percentages of improvement in blood glucose level of our synthesized
anti-diabetic compounds and gliclazide as reference drug.
Percentage of Improvement
Mean of disease Mean of treated
=
X100
Mean of control
Significant increase in blood glucose level was noticed in diabetic
rats compared to normal control with percentage increase 330%.
Silicate coated particles ofcompounds1c and 5declared highest im-
provement percentages in blood glucose levels reach to 302.65 and
309.71%, respectively (Table 3).
2.3. Evaluation of the biological activity
2.3.2. Liver function enzyme activities
Aminotransferases (ALT and AST) and ALP activity were markedly
elevated in STZ-treated animals. High blood glucose level resulted in
hepatolysis which reflected by high aminotransferases activity as a
leading cause of diabetic complication. Hepatic enzymes exhibited
significant elevation in serum of diabetic rats recorded percentages
64.07, 89.38 and 169.55%, respectively, for AST, ALT and ALP.
Compounds 1c and5showed marked amelioration in blood glucose
level. Upon treated diabetic rats with compounds 1c and 5 more or less
similar results were observed for hepatic enzyme activities in compar-
ison with gliclazide (Table 4). Silicate coated particles of compounds1c
and 5 coated by TEOS exhibited higher improvement in the hepatic
enzymes effect compared to their relative silicate coated particles of
gliclazide. The comparison between the AST, ALT, ALP enzyme activ-
ities of our synthesized compounds and gliclazide as a reference anti-
diabetic agent is illustrated graphically in Fig. 3.
2.3.1. Streptozotocin-induced hyperglycemia
Streptozotocin with certain dose cause partially pancreatic β-cells
damage. In addition, breakdown of glycogen from liver is responsible
for the enhancement in gluconeogensis. Anti-diabetic properties of the
synthesized sulfonyl urea derivatives were carried out. From the ob-
tained results it was noticed that, compounds 1c and 5 recorded sig-
nificant reduction in blood glucose level compared to diabetic rats with
highest reduction in blood glucose level in comparison with that of
standard drug (gliclazide, MR60), which is classified as a third gen-
eration sufonylurea derivatives [15]. Additionally, an insignificant
difference in blood glucose level was observed for the other tested
compounds (Table 2). Percentages of improvement in blood glucose
level of our synthesized anti-diabetic compounds and gliclazide as re-
ference drug (Fig. 2).
Mean of treated Mean of control
Percentage Change =
X100
2.3.3. Profile of lipid
Mean of control
The current study showed dramatic increment in TG, TC and TL
levels in diabetic rats. This elevation may be due to activation of li-
poprotein lipase by insulin which decomposes triglycerides. Deficiency
Table 2
Effects of different synthesized compounds on blood glucose level in STZ in-
duced diabetic rats.
Table 3
Comparative effects between normal and silicate coated particles among com-
Groups
Parameters
pounds 1c, 5 and gliclazide on blood glucose level in STZ-induced diabetic rats.
Blood glucose level (mg/dL)
% Change
% Improvement
Groups
Parameters
Control
90.60
5.90f
–
–
Blood glucose level
(mg/dL)
% Change % Improvement
Diabetic
389.80
365.20
213.60
345.80
348.80
328.24
329.00
200.6
9.77 g
7.25 g
9.90 h
8.70 g
12.50 g
6.70 g
10.20 g
11.27 h
10.17e
330.24
303.09
135.76
281.68
284.99
262.29
263.13
121.41
197.57
–
1b
27.15
194.48
48.56
45.25
67.95
67.11
208.83
132.67
1c
Control
Diabetic
1c
90.60
5.90
9.77
9.90
6.22
–
–
1f
389.80
213.60
330.24
135.76
20.53
–
1 g
Normal form
194.49
309.71
2
Silicate coated 109.2
particles
3
5
5
Normal form
200.6
11.27
9.00
121.41
27.59
208.83
302.65
Gliclazide
269.60
Silicate coated 115.6
particles
Data are given in mean
SD from 10rats in each group. Values in parentheses
Gliclazide Normal form
269.60
10.1
7.22
197.57
86.53
132.67
243.70
represent % of improvements from control. Statistical analysis are carried out
using one way analysis of variance (ANOVA) using Co-Stat Computer program,
where unshared letters are significant at p ≤ 0.05.
Silicate coated 169.0
particles
3

F.M. Sroor, et al.
BioorganicChemistry92(2019)103290
180
160
140
120
100
80
AST
ALT
ALP
60
40
20
0
1c
1c (coated)
5
5 (coated) Gliclazide Gliclazide
(coated)
Fig. 3. Comparison of the AST, ALT, ALP activities among 1c, 5 compounds and
gliclazide as standard anti-diabetic reference drug.
of insulin leads to fail in the activation of lipase enzyme, hence, causing
hypertriglyceridemia. Marked elevation in lipid profile; TC, TG and TL
levels (relative to control) in diabetic rats with percentages 214.74,
239.01 and 136.65%, respectively was observed (Table 5). Obvious
improvement in lipid profile levels was noticed upon treatment of the
diabetic rats with compounds 1c and 5 in comparison with gliclazide-
reached to 171.98, 87.35 and 61.68%, respectively for 1c and182.74,
119.12 and 86.65%, respectively for compound 5. Silicate coated par-
ticles of compound 1c exhibited higher improvement recorded 209.57,
204.46 and 122.49%, respectively in comparison with that of gliclazide
(200.73, 183.17 and 109.16%, respectively). While, an interesting si-
licate coated particles of compound 5exhibited higher improvement
percentages for TC, TG and TL at 212.36, 217.37, and 131.83%. The
comparison between the TG, TC and TL profiles of compounds 1c, 5 and
gliclazidewas showed graphically in Fig. 4.
2.3.4. Antioxidants study
The antioxidant defense systems are represented in two ways either
enzymatic or non-enzymatic. In diabetes mellitus, the oxidative stress
can be resulted from the increased production of free radicals with/or a
marked reduction of antioxidant defenses including enzymatic and non-
enzymatic antioxidant. Noticeable improvement in the antioxidant
enzyme levels, GSH content as well as MDA level upon treatment of
diabetic rats with compounds 1c and 5compared to their corresponding
standard drug (Tables 6 and 7). However, compound 5 showed more
effect than 1c compared to standard drug. Silicate coated particles of
compounds 1c and5 showed more potent effect than their corre-
sponding normal form in ameliorating oxidative stress marker, MDA
and antioxidant enzymes as well as hepatic GSH. In general, compound
5 showed higher effect than 1c, while silicate coated particles of
compound 5 showed the highest effect compared to its relative silicate
coated particles standard drug as shown in Fig. 5.
2.3.5. Histopathological studies
2.3.5.1. Histopathological examination of liver. As shown in Table 8 and
Fig. 6. Liver of control rats (G1) rats demonstrated the normal structure
of hepatic lobule. Hepatic architecture of diabetic rats (G2) declared
congestion of hepatic sinusoids, cytoplasmic vacuolation of hepatocytes
and fibroplasia in the portal triad. Diabetic rats treated with 1c (G3)
exhibited central vein congestion and hepatic sinusoids, slight
congestion of hepatic sinusoids and congestion of hepato portal blood
vessel. Liver of diabetic rats treated with silicate coated nanoparticles of
compound 1c (G4) showed no histopathological changes, while Kupffer
cells activation were noticed. Liver of diabetic rats treated with
compound 5 (G5) showed cytoplasmic vacuolation of hepatocytes,
congestion of central vein and hepatic sinusoids. Liver of diabetic rats
treated with silicate coated nanoparticles of compound 5 (G6) showed
slight hydropic degeneration of hepatocytes. Liver of diabetic rats
treated with gliclazide (G7) showed Kupffer cells activation. Liver of
diabetic rats treated with silicate coated nanoparticles of gliclazide (G8)
4

F.M. Sroor, et al.
BioorganicChemistry92(2019)103290
Table 5
Comparative effects among compounds 1c, 5 and gliclazide (normal and silicate coated particles-forms) on TC, TG and TL levels.
Groups
Parameters
TC
TG
TL
mg/dL
% Change % Improvement mg/dL
% Change % Improvement mg/dL
% Change % Improvement
Control
Diabetic
1c
88.10
277.29
5.01b
–
–
31.38
106.38
78.97
42.22
69.00
38.17
75.97
48.90
6.79b
–
–
600.10
1420.14
1050.00
685.10
900.13
629.00
1102.20
765.10
18.00b
22.0a
–
–
14.76a 214.74
11.90c 42.77
–
6.36a 239.01
–
136.65
–
Normal form 125.78
171.98
209.57
182.74
212.36
157.76
200.73
7.33f
151.66
34.54
87.35
204.46
119.12
217.37
96.91
183.17
23.00e 74.97
61.68
122.49
86.65
131.83
52.98
109.16
Nano form
92.66
9.76b
5.18
3.60e
13.00b
21.00c
33.00b
14.16
50.00
4.82
5
Normal form 116.30
Nano form 90.20
12.80c 32.01
7.60c
119.89
11.80b
2.380
8.69 h 21.64
Gliclazide Normal form 138.29
12.90e 56.97
2.69f
142.10
29.00e 83.67
18.00 h 27.50
Nano form
100.45
7.80b
14.02
3.60 g 55.83
Results are given in mean
SD from 15 rats in each group. Values in parentheses represent % of improvements from control.Statistical analysis are carried out using
one way analysis of variance (ANOVA) using Co-Stat Computer program, where unshared letters are significant at p ≤ 0.05.
glomerular tuft while the remained slides exhibited no structural
200
150
100
50
changes. Kidney of diabetic rats treated with gliclazide (G7) showed
no changes. In some slides showed congestion of renal blood vessel.
Kidney of diabetic rats treated with silicate coated nanoparticles of
gliclazide (G8) showed no histopathological changes.
TC
TG
TL
2.3.5.3. Histopathological examination of Pancreas. As shown in
Table 10 and Fig. 7. Pancreas of rat (G1) revealed no changes.
Pancreas of diabetic rats (G2) exhibited vacuolation of islets of
Langerhan’s cells of and focal hemorrhage. Pancreas of diabetic rat
treated with compound 1c (G3) demonstrated vacuolation of some cells
of islets of Langerhan’s. Pancreas of diabetic rat treated with silicate
coated particles of compound 1c (G4) showed no structural changes.
Pancreas of diabetic rat treated with compound 5 (G5) declared no
changes. In some slides vacuolation of few cells of islets of Langerhan’s
were appeared. Pancreas of diabetic rat treated with silicate coated
particles of compound 5 (G6) showed no histopathological changes in
some slides necrosis of sporadic cells of islets of Langerhan’s were
appeared. Pancreas of diabetic rats treated with gliclazide (G7) showed
no histopathological changes. In some slides slight congestion of
pancreatic blood vessel were appeared. Pancreas of diabetic rats
treated with silicate coated nanoparticles of gliclazide (G8) showed
no histopathological changes as shown in Fig. 8.
0
1c
1c (coated)
5
5 (coated) Gliclazide Gliclazide
(coated)
Fig. 4. Comparison of the lipid profile TC, TG and TL levels among compounds
1c, 5 and gliclazide.
showed no histopathological changes.
2.3.5.2. Histopathological examination of kidneys. As shown in Table 9
and Fig. 7. Kidney of control rats showed normal structure of renal
parenchyma (G1). Diabetic rat demonstrated vacuolation of epithelial
lining renal tubules and cystic dilatation of renal tubules (G2). Kidney
of diabetic rats treated with1c (G3) showed in some slides congestion of
renal blood vessels while the remained slides declared no structural
changes. Kidney of diabetic rats treated with silicate coated
nanoparticles of compound 1c (G4) showed no histopathological
change. Kidney of diabetic rats treated withcompound5 (G5) showed
no histopathological changes. Kidney of diabetic rats treated with
silicate coated particles of compound 5 (G6) showed in some slides
vacuolation of epithelial lining renal tubules and congestion of
2.4. Single crystal X-ray diffraction
A single Crystals suitable for X-ray diffraction analysis were ob-
tained from a saturated ethylacetate solution at room temperature. The
X-ray crystal structures were determined by using
a Rigaku
R-AXISRAPID diffractometer and Bruker X8 Prospector. The collection
of single crystal data was made at room temperature by using Cu-Kα
radiation. The structures were solved by using direct methods and
Table 6
Comparative effects among compounds 1c, 5 and gliclazide on enzymatic antioxidants.
Groups
Parameters
CAT
SOD
GST
µMol/min/mg
protein
% Change % Improvement µMol/min/mg
protein
% Change % Improvement mmol/min/mg
protein
% Change % Improvement
Control
Diabetic
1c
9.40
3.04
0.15a
0.10b
0.40c
0.12d
0.20c
0.06d
0.19b
0.04c
–
–
52.35
15.73
27.70
44.94
27.34
44.39
20.80
31.45
6.80a
1.22b
4.50c
5.50d
3.29c
4.26d
2.12b
3.01c
–
–
790.34
230.39
497.80
623.30
560.70
636.60
490.20
580.03
31.56a
27.34b
21.90e
28.59d
23.44c
25.42d
18.35e
20.33c
–
–
−67.66
−37.23
−26.60
−38.30
−25.00
−58.51
−45.11
–
−69.95
−47.08
−14.14
−47.76
−15.19
−60.26
−39.91
–
169.55
10.83
46.38
−7.06
51.84
39.45
65.12
–
Normal form 5.90
30.43
41.06
29.36
42.66
9.15
22.55
22.87
55.81
22.18
54.76
9.69
30.03
33.83
49.71
41.79
51.39
32.87
44.23
Nano form
6.90
5
Normal form 5.80
Nano form 7.05
Gliclazide Normal form 3.90
Nano form 5.16
5

F.M. Sroor, et al.
BioorganicChemistry92(2019)103290
140
120
100
80
CAT
SOD
GST
GPx
GSH
MDA
60
40
20
0
1c
1c
(coated)
5
5
Gliclazide Gliclazide
(coated) (coated)
Fig. 5. Percentages of improvement of antioxidant and oxidative stress bio-
markers using compounds 1c, 5 and gliclazide.
expanded using Fourier techniques. Thenon-hydrogen atoms were re-
fined anisotropically [28].
The structure was solved and refined using the Bruker SHELXTL
Software Package, using the space group P 1 21/n 1, with Z = 4 for the
formula unit, C14H12Cl2N2O3S. The final anisotropic full-matrix least-
squares refinement on F2 with 200 variables converged at R1 = 5.37%,
for the observed data and wR2 = 14.54% for all data. The goodness-of-
fit was 1.110. The largest peak in the final difference electron density
synthesis was 0.507 e−/Å3 and the largest hole was −0.770 e−/Å3
with an RMS deviation of 0.120 e−/Å3. On the basis of the final model,
the calculated density was 1.477 g/cm3 and F(000), 736 e−.The CCDC
number is 1883953.
3. Conclusions
In summary, the treatment of sulfonyl isocyanate with selected
amino derivatives afforded newer sulfonylurea derivatives 1–5 that
showed a significant anti-diabetic properties. The results indicated that
the synthesized derivatives revealed decrease in the mean blood glu-
cose for rats previously induced with diabetes mellitus type 2. It was
noticed also, the silicate coated nanoparticles of the active compounds
1c and 5 enhanced the biological properties and it is considered as
potential lead compounds in diabetes treatment as comparison to gli-
clazideas a reference drug.
4. Experimental
4.1. Chemistry
All melting points are recorded on digital Gallen Kamp MFB-595
instrument and may be uncorrected. The IR spectra (KBr) (cm−1) were
measured on a JASCO spectrophotometer. 1H NMR spectra were re-
corded on Bruker spectrometers (400 MHz) and are reported relative to
deuterated solvent signals in deuterateddimethylsulfoxide (DMSO‑d6).
13C NMR spectra were recorded on Bruker Spectrometers (100 MHz) in
deuterateddimethylsulfoxide (DMSO‑d6).
4.1.1. N-(arylcarbamoyl)-4-methylbenzenesulfonamide
To a solution of requisite amines (0.01 mol) in acetonitrile (in case
of compound 3, dichloromethane was used) (20 mL), p-methylbenze-
nesulfonylisocyanate (0.01 mol) was added while stirring at room
temperature. The reaction mixture was stirred to the desired time, by
following with TLC. The obtained precipitate was filtered off, washed
with cold acetonitrile (two times) dried well, and recrystallized from
ethanol to give:
4.1.1.1. N-(3-Chlorophenylcarbamoyl)-4-methylbenzenesulfonamide [16]
(1a). Yield 95%; m.p. 188–190 °C. IR (KBr, cm−1): 3314, 3283 (NH),
1683 (C]O), 1347, 1167 (SO2). 1H NMR (DMSO‑d6, δ): 2.41 (s, 3H,
6

F.M. Sroor, et al.
BioorganicChemistry92(2019)103290
Table 8
Tesion score of liver for diabetic and treated diabetic rats with tested compounds.
Groups
Parameters
Histopathological lesion
Kupffer cells
activation
Congestion of central vein &
sinusoids
Vacuolation of
hepatocytes
Hydropic degeneration of
Portal fibroplasia
hepatocytes
Normal control
Diabetic
–
–
–
–
–
–
–
–
++
+
+++
++
–
++
++
1c
Normal form
–
–
–
–
Silicate coated
particles
+
5
Normal form
Silicate coated
particles
+
–
++
–
++
–
–
–
–
++/+
Gliclazide Normal form
Silicate coated
+
–
+
–
–
–
–
–
–
–
particles
(–) normal histological structure, (+) mild change, (++) moderate change, (+++) severe change.
CH3),7.07 (d, 1H, J = 8 Hz, Ar-H),7.13–7.32 (m, 2H, Ar-H), 7.43(d, 2H,
J = 8 Hz, Ar-H), 7.52 (s, 1H, Ar-H), 7.87 (d, 2H, J = 8 Hz, Ar-H), 8.90
(br, 1H, NH), 9.60 (br, 1H, NH). Anal. For C14H13ClN2O3S: Calcd. C,
51.77; H, 4.03; N, 8.63. Found: C, 51.85; H, 3.98; N, 8.54.
1666 (C]O), 1347, 1164 (SO2). 1H NMR (DMSO‑d6, δ): 2.38 (s,3H,
CH3), 7.21–7.50 (m, 5H, Ar-H), 7.72 (d, 1H, J = 8.0 Hz, Ar-H), 7.84 (d,
1H, J = 8.0 Hz, Ar-H), 8.45 (br, 1H, NH), 11.17 (br, 1H, NH). 13C NMR
(DMSO‑d6, δ): 21.5, 117.5, 118.8, 126.1, 127.7, 128.9, 129.8, 132.4,
134.5, 137.7, 141.5, 142.3, 144.2, 149.8. Anal. For C14H12Cl2N2O3S:
Calcd. C, 46.81; H, 3.37; N, 7.80. Found: C, 46.64; H, 3.41; N, 7.69.
4.1.1.2. 4-Methyl-N-(4-(phenyldiazenyl)phenylcarbamoyl)
benzenesulfonamide (1b). Yield 87%; m.p. 208–210 °C. IR (KBr, cm−1):
3317, 3275 (NH), 1698 (C]O), 1346, 1197 (SO2). 1H NMR (DMSO‑d6,
δ): 2.41 (s, 3H, CH3), 7.45 (d, 2H, J = 8 Hz, Ar-H), 7.48–7.62 (m, 5H,
Ar-H), 7.85 (m, 4H, Ar-H), 7.89 (d, 2H, J = 8 Hz, Ar-H), 9.13 (br, 1H,
NH), 10.75 (br, 1H, NH).13C NMR (DMSO‑d6, δ): 21.5, 113.9, 119.6,
122.2, 122.8, 124.4, 125.6, 126.1, 128.0, 129.8, 131.5, 137.6, 141.7,
144.4, 148.1, 149.8, 152.6, 153.2. Anal. For C20H18N4O3S: Calcd. C,
60.90; H, 4.60; N, 14.20. Found: C, 60.85; H, 4.58; N, 14.14.
4.1.1.4. 4-Methyl-N-(2-methyl-5-nitrophenylcarbamoyl)
benzenesulfonamide (1d). Yield 66%; m.p. 220–223 °C. IR (KBr, cm−1):
3329 (NH), 1692 (C]O), 1344, 1149 (SO2). 1H NMR (DMSO‑d6, δ):
2.28 (s, 3H, CH3), 2.41 (s, 3H, CH3), 7.45 (m, 3H, Ar-H), 7.88 (m, 3H,
Ar-H), 8.34(s, 1H, Ar-H), 8.61 (br, 1H, NH), 11.06 (br, 1H, NH). 13C
NMR (DMSO‑d6, δ): 18.1, 21.5, 107.6, 110.7, 115.1, 118.7, 126.1,
127.9, 130.0, 131.7, 136.4, 137.3, 144.6, 146.5, 149.9. Anal. For
C15H15N3O5S: Calcd. C, 51.57; H, 4.33; N, 12.03. Found: C, 51.63; H,
4.28; N, 12.09.
4.1.1.3. N-(2,6-Dichlorophenylcarbamoyl)-4-methylbenzenesulfonamide
(1c). Yield 95%; m.p. 180–182 °C. IR (KBr, cm−1): 3272, 3231 (NH),
Fig. 6. Liver sections of control rats (G1) showing the normal structure of hepatic lobule. Liver of diabetic rats (G2) revealing congestion of hepatic sinusoids
cytoplasmic, fibroplasia in the portal triad and vacuolation of hepatocytes. Liver of diabetic rats treated with 1c (G3) showing some cytoplasmic vacuolation of
hepatocytes also few congestion of central vein and enhanced most hepatic cells. Liver of diabetic rats treated with silicate coated nanoparticles of compound 1c (G4)
showing hepatic cells nearly control while few congestion of central vein. Liver of diabetic rats treated with compound 5 (G5) showing no histopathological changes
with Kupffer cells activation. Liver of diabetic rats treated with silicate coated nanoparticles of compound 5 (G6) showing slight hydropic degeneration of hepatic
cells. Liver of diabetic rats treated with gliclazide (G7) showing no histopathological changes with some Kupffer cells activation. Liver of diabetic rats treated with
silicate coated nanoparticles of gliclazide (G8) showing no histopathological changes with normal hepatic cells (H & E × 200).
7

F.M. Sroor, et al.
BioorganicChemistry92(2019)103290
Table 9
Lesion score of kidney of diabetic and diabetic-treated rats with the tested compounds.
Groups
Parameters
Histopathological lesion
Congestion of renal blood vessels
Vacuolation of renal tubules
Congestion of glomerular tuft
Cystic dilatation of renal tubules
Normal control
Diabetic
–
–
–
–
++
++
++
++
1c
Normal form
++
–
–
–
–
–
–
–
–
silicate coated particles
Normal form
–
–
–
5
–
–
–
silicate coated particles
Normal form
–
+
–
+
–
Gliclazide
+
–
silicate coated particles
–
–
(–) normal histological structure, (+) mild change, (++) moderate change, (+++) severe change
4.1.1.5. 4-Methyl-N-(4-methyl-3-nitrophenylcarbamoyl)
δ): 2.28 (s, 3H, CH3), 2.40 (s, 3H, CH3), 7.42 (d, 2H, J = 8 Hz, Ar-H),
7.50 (s, 2H, Ar-H), 7.84 (d, 2H, J = 8 Hz, Ar-H), 8.24(br, 1H, NH),
10.92 (br, 1H, NH). 13C NMR (DMSO‑d6, δ): 20.2, 21.5, 108.2, 124.5,
126.1, 127.8, 129.7, 132.6, 137.8, 141.1, 142.3, 144.2, 149.8. Anal. For
C15H14Br2N2O3S: Calcd. C, 38.98; H, 3.05; N, 6.06. Found: C, 39.05; H,
3.07; N, 5.89.
benzenesulfonamide (1e). Yield 58%; m.p. 204–205 °C. IR (KBr, cm−1):
3288, 3195 (NH), 1694 (C]O), 1350, 1165 (SO2). 1H NMR (DMSO‑d6,
δ): 2.41 (s, 3H, CH3), 2.44 (s, 3H, CH3), 7.39 (d, 1H, J = 8 Hz, Ar-H),
7.44 (d, 2H,J = 8 Hz, Ar-H), 7.51 (d, 1H, J = 8 Hz, Ar-H), 7.87 (d, 2H,
J = 8 Hz, Ar-H), 8.10(s, 1H, Ar-H), 9.12 (br, 1H, NH), 10.75 (br, 1H,
NH). 13C NMR (DMSO‑d6, δ): 19.3, 21.5, 108.7, 114.7, 119.5, 124.2,
126.1, 128.0, 130.0, 133.5, 137.6, 144.4, 149.2, 150.0. Anal. For
C15H15N3O5S: Calcd. C, 51.57; H, 4.33; N, 12.03. Found: C, 51.65; H,
4.29; N, 11.94.
4.1.1.8. N-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-
ylcarbamoyl)-4-methyl Benzenesulfonamide (2). Yield 62%; m.p.
150–152 °C. IR (KBr, cm−1): 3433, 3120 (NH), 1629 (C]O). 1H NMR
(DMSO‑d6, δ): 2.08 (s,3H, CH3),2.41(s,3H, CH3),3.04 (s,3H, CH3),7.34
(m, 3H, Ar-H), 7.42 (d, 2H, J = 8.0 Hz, Ar-H), 7.50 (t, 2H, J = 7.9 Hz,
Ar-H), 7.64 (br, 1H, NH), 7.85 (d, 2H, J = 8.0 Hz, Ar-H), 10.67 (br, 1H,
NH). 13C NMR (DMSO‑d6, δ): 9.2, 19.4, 34.2, 104.8, 116.3, 120.4,
122.2, 124.8, 125.8, 127.5, 127.8, 133.3, 135.7, 142.2, 148.9, 150.2,
160.0. Anal. For C19H20N4O4S: Calcd. C, 56.99; H, 5.03; N, 13.99.
Found: C, 57.11; H, 5.00; N, 13.86.
4.1.1.6. N-(5-Chloro-2-hydroxyphenylcarbamoyl)-4-
methylbenzenesulfonamide (1f). Precipitate was obtained after
treatment with cold water, yield 73%; m.p. 198–200 °C. IR (KBr,
cm−1): 3483, 3373, 3329, 3209 (NH & OH), 1706, 1680 (C]O),
1345, 1155 (SO2). 1H NMR (DMSO‑d6, δ): 2.41 (s, 3H, CH3), 6.85 (m,
2H, Ar-H), 7.44 (d, 2H, J = 8 Hz, Ar-H), 7.85 (m, 3H, Ar-H), 8.46 (br,
1H, NH), 10.28 (br, 1H, NH), 10.90 (br, 1H, OH). Anal. For
C
14H13ClN2O4S: Calcd. C, 49.34; H, 3.85; N, 8.22. Found: C, 49.25;
4.1.1.9. 4-Methyl-N-(ricycle[3.3.1.13,7]dec-1-ylcarbamoyl)
benzenesulfonamide(3). Yield 61%; m.p. 150–152 °C. IR (KBr, cm−1):
3425, 3343 (NH), 2911 (CH-aliph.), 1700 (C]O), 1371, 1132 (SO2). 1H
NMR (DMSO‑d6, δ): 1.51–2.13(m, 15H, adamantyl), 2.38 (s,3H, CH3),
6.03 (br., 1H, NH), 7.27 (br., 1H, NH), 7.36 (d, 2H, J = 8 Hz,Ar-H),
7.72 (d, 2H, J = 8 Hz, Ar-H). 13C NMR (DMSO‑d6, δ): 21.4, 28.8, 29.3,
H, 3.81; N, 8.13.
4.1.1.7. N-(2,6-Dibromo-4-methylphenylcarbamoyl)-4-
methylbenzenesulfonamide (1 g). Yield 52%; m.p. 238–240 °C. IR (KBr,
cm−1): 3269 (NH), 1671(C]O), 1353, 1170 (SO2). 1H NMR (DMSO‑d6,
Fig. 7. Kidney of control rats showed the normal histological structure of renal parenchyma (G1). Kidney of diabetic rat showed vacuolation of epithelial lining renal
tubules and cystic dilatation of renal tubules (G2). Kidney of diabetic rats treated with 1c (G3) showed in some slides congestion of renal blood vessels while the
remained slides showed no histopathological changes. Kidney of diabetic rats treated with silicate coated nanoparticles of compound 1c (G4) showed no histo-
pathological change. Kidney of diabetic rats treated with compound 5 (G5) showed no histopathological changes. Kidney of diabetic rats treated with silicate coated
particles of compound 5 (G6) showed in some slides vacuolation of epithelial lining renal tubules and congestion of glomerular tuft while the remained slides showed
no histopathological changes. Kidney of diabeticrats treated with gliclazide (G7) showed no histopathological changes. In some slides showed congestion of renal
blood vessel. Kidney of diabetic rats treated with silicate coated nanoparticles of gliclazide (G8) showed no histopathological changes.
8

F.M. Sroor, et al.
BioorganicChemistry92(2019)103290
Table 10
Lesion score of pancreas of diabetic and diabetic-treated rats with tested the compounds.
Groups
Parameters
Histopathological lesion
Congestion of pancreatic blood
vessels
Necrosis of cells of islets of
Langerhan’s
Vacuolation of cells of islets of
Focal haemorrhage
Langerhan’s
Normal control
Diabetic
–
–
–
–
+
–
+
–
++
++
–
++
1c
Normal form
–
–
Silicate coated
particles
–
–
5
Normal form
Silicate coated
particles
–
–
–
+
–
–
–
+
Gliclazide Normal form
Silicate coated
+
–
–
–
–
–
–
–
particles
(–) normal histological structure, (+) mild change, (++) moderate change, (+++) severe change.
35.5, 36.4, 41.7, 50.6, 126.1, 127.4, 129.8, 141.9, 142.3. Anal. For
(DMSO‑d6, δ): 1.77 (m, 4H, 2CH2), 2.39 (s, 3H, CH3), 3.25 (m, 4H,
2CH2), 7.38 (d, 2H, J = 8.0 Hz, Ar-H), 7.82 (d, 2H, J = 8.0 Hz, Ar-H),
10.41 (br, 1H, NH). 13C NMR (DMSO‑d6, δ): 21.4, 25.2, 46.3, 128.0,
129.5, 138.6, 143.6, 150.9. Anal. For C12H16N2O3S: Calcd. C, 53.71; H,
6.01; N, 10.44. Found: C, 53.64; H, 5.98; N, 10.51.
C
18H24N2O3S: Calcd. C, 62.04; H, 6.94; N, 8.04. Found: C, 62.11; H,
6.91; N, 7.92.
4.1.1.10. 2-(2-(1H-Indol-3-yl)acetyl)-N-tosylhydrazinecarboxamide
(4). Yield 62%; m.p. 150–152 °C. IR (KBr, cm−1): 3401 (NH), 1732
(C]O), 1380, 1114 (SO2). 1H NMR (DMSO‑d6, δ): 2.40 (s, 3H, CH3),
3.53 (s, 2H, CH2), 6.97 (m, 1H, Ar-H), 7.07 (t, 1H, J = 8.0 Hz, Ar-H),
7.20 (s, 2H, Ar-H), 7.30–7.45 (m, 3H, Ar-H & NH), 7.55 (m, 1H, Ar-H),
7.73 (d, 1H, J = 8 Hz, Ar-H), 7.82 (d, 2H, J = 8.0 Hz, Ar-H), 8.35 (br,
1H, NH), 9.78 (br, 1H, NH), 10.80 (br, 1H, NH). 13C NMR (DMSO‑d6, δ):
21.5, 30.9, 108.4, 111.7, 118.8, 119.1, 121.4, 124.3, 126.1, 127.8,
129.7, 129.8, 136.6, 137.8, 142.3, 144.2, 152.1, 170.6. Anal. For
4.2. Biochemical studies of the synthesized products
The diabetic rats was orally administrated 150 mg/kg body weight
of synthetic organic compounds in both normal and nanoforms for
30 days [3]. Likewise, the diabetic rats was orally administrated anti-
diabetic gliclazide reference drug 150 mg/kg body weight daily for
30 days [4].Blood glucose level was measured in blood serum according
to the method of Trinder [17]. Liver function enzyme activities, alanine
and aspartate amino tranferases (AST and ALT) as well as alkaline
phosphatase (ALP) were determined in mice serum according to the
Reitman [18] and Belfield [19] methods. Serum total lipids con-
centration was determined according to the method of Zollner [20],
serum triglyceride (TG) concentration was determined according to the
C
18H18N4O4S: Calcd. C, 55.95; H, 4.70; N, 14.50. Found: C, 56.04; H,
4.72; N, 14.54.
4.1.1.11. N-[(4-Methylphenyl)sulfonyl]pyrrolidine-1-carboxamide
(5). Yield 93%; m.p. 228–230 °C. IR (KBr, cm−1): 3267 (NH), 2976,
2935, 2879 (CH-aliph.), 1695 (C]O), 1367, 1090 (SO2). 1H NMR
Fig. 8. Pancreas of rat (G1) showed no histopathological changes. Pancreas of diabetic rats (G2) showed vacuolation of cells of islets of Langerhan’s and focal
haemorrhage. Pancreas of diabetic rat treated with compound 1c (G3) showed vacuolation of some cells of islets of Langerhan’s. Pancreas of diabetic rat treated with
silicate coated particles of compound 1c (G4) showed no histopathological changes. Pancreas of diabetic rat treated with compound 5 (G5) showed no histo-
pathological changes. In some slides vacuolation of few cells of islets of Langerhan’s were appeared. Pancreas of diabetic rat treated with silicate coated particles of
compound 5 (G6) showed no histopathological changes in some slides necrosis of sporadic cells of islets of Langerhan’s were appeared. Pancreas of diabetic rats
treated with gliclazide (G7) showed no histopathological changes. In some slides slight congestion of pancreatic blood vessel were appeared. Pancreas of diabetic rats
treated with silicate coated nanoparticles of gliclazide (G8) showed no histopathological changes.
9

F.M. Sroor, et al.
BioorganicChemistry92(2019)103290
method of Fassati and Prencipe [21] and serum total cholesterol con-
centration was estimated according to the method of Allain [22]. Liver
nitrite (NO) level was estimated [23]. GSH level was assayed in liver
homogenate according to Beutler method [24] Liver MDA level was
estimated according to the method of Satoh [25]. GR was determined
according to the method of Goldberg and Spooner [26] and SOD ac-
cording to the Nishikimi et al. [27].
pot synthesis catalyzed by tetrachlorosilane, Egypt. J. Chem. 56 (2013) 291–305.
[9] F.M. Sroor, T.K. Khatab, W.M. Basyouni, K.A.M. El-Bayouki, Synthesis and mole-
cular docking studies of some new thiosemicarbazone derivatives as HCV poly-
merase inhibitors, Synth. Comm. 49 (2019) 1444–1456.
[10] A.S. Hassan, D.M. Masoud, F.M. Sroor, A.A. Askar, Synthesis and biological eva-
luation of pyrazolo[1,5-a]pyrimidine-3-carboxamide as antimicrobial agents, Med.
Chem. Res. 26 (2017) 2909–2919.
[11] F.M. Sroor, C.G. Hrib, L. Hilfert, S. Busse, F.T. Edelmann, Synthesis and catalytic
activity of homoleptic lanthanide-tris(cyclopropylethinyl)amidinates, New J. Chem.
39 (2015) 7595–7601.
[12] F.M. Sroor, C.G. Hrib, L. Hilfert, P.G. Jones, F.T. Edelmann, Lanthanide(III)-bis
(cyclopropylethinylamidinates): Synthesis, structure, and catalytic activity, J.
Organomet. Chem. 785 (2015) 1–10.
Acknowledgments
[13] F.M. Sroor, C.G. Hrib, L. Hilfert, L. Hartenstein, P.W. Roesky, F.T. Edelmann,
Synthesis and structural characterization of new bis(alkynylamidinato)lanthanide
(III)-amides, J. Organomet. Chem. 799–800 (2015) 160–165.
This work was supported by the National Research Centre (NRC)
under project number 11010338. We are grateful to Dr. Wael M.
Tohamy for the help in the X-ray diffraction.
[14] C.P. Price, A.L. Grzesiak, A.J. Matzger, Crystalline polymorph selection and dis-
covery with polymer heteronuclei, J. Am. Chem. Soc. 127 (2005) 5512–5517.
[15] D.R. Webb, M. Davies, K. Khunti, Sulfonylureas: historic to contemporary role in the
management of type 2 diabetes, Medicographia 40 (2018) 129–135.
[16] J.J. Howbert, C.S. Grossman, T. Crowell, B.J. Rieder, R.W. Harper, K.E. Kramer,
E.V. Tao, J. Aikins, G.A. Poore, S.M. Rinzel, G.B. Grindey, W.N. Shaw, G.C. Todd,
Novel agents effective against solid tumors: the diarylsulfonylureas. Synthesis, ac-
tivities, and analysis of quantitative structure-activity relationships, J. Med. Chem.
33 (1990) 2393–2407.
Appendix A. Supplementary material
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.bioorg.2019.103290.
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