Design and synthesis of hydrazinecarbothioamide sulfones as potential antihyperglycemic agents

Article abstract of DOI:10.1002/ardp.202000336

New hydrazinecarbothioamides with a phenylsulfonyl group were synthesized and their structures were identified by different spectroscopic data (¹H NMR, ¹³C NMR, two-dimensional?NMR, mass spectrometry, elemental analysis, and single-crystal X-ray analysis). The mechanism describing the formation of the products was also discussed. The antidiabetic activity of the isolated products was investigated histochemically. The synthesized sulfonylalkylthiosemicarbazide exhibited antihyperglycemic activity in streptozotocin-induced diabetic mice. Compounds?5a and 5c?significantly lowered the blood glucose level to 103.3 ± 1.8 and 102 ± 3.9 mg/dl, respectively. Also, they caused a significant decrease in malondialdehyde levels and normalized the glutathione levels in streptozotocin-induced diabetic mice, compared with the diabetic group. The results suggest that the synthesized hydrazinocarbothioamides may effectively inhibit the development of oxidative stress in diabetes.

Full text of DOI:10.1002/ardp.202000336

Received: 6 September 2020
DOI: 10.1002/ardp.202000336
Revised: 10 November 2020
Accepted: 5 December 2020
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F U L L P A P E R
Design and synthesis of hydrazinecarbothioamide sulfones as
potential antihyperglycemic agents
Ashraf A. Aly1
| Alaa A. Hassan1 | Maysa M. Makhlouf1
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Mohammed B. Alshammari2 | Sara Mohamed Naguib Abdel Hafez3
|
Marwa M. M. Refaie4
| Stefan Bräse5,6
| Martin Nieger7 | Mohamed Ramadan8
1Department of Chemistry, Faculty of Science,
Minia University, El‐Minia, Egypt
Abstract
2Prince Sattam bin Abdulaziz Department of
Chemistry, College of Sciences and
Humanities, Alkharj, Saudi Arabia
New hydrazinecarbothioamides with a phenylsulfonyl group were synthesized and their
structures were identified by different spectroscopic data (1H NMR, 13C NMR,
two‐dimensional NMR, mass spectrometry, elemental analysis, and single‐crystal X‐ray
analysis). The mechanism describing the formation of the products was also discussed.
The antidiabetic activity of the isolated products was investigated histochemically. The
synthesized sulfonylalkylthiosemicarbazide exhibited antihyperglycemic activity in
streptozotocin‐induced diabetic mice. Compounds 5a and 5c significantly lowered the
blood glucose level to 103.3 1.8 and 102 3.9 mg/dl, respectively. Also, they caused a
significant decrease in malondialdehyde levels and normalized the glutathione levels in
streptozotocin‐induced diabetic mice, compared with the diabetic group. The results
suggest that the synthesized hydrazinocarbothioamides may effectively inhibit the
development of oxidative stress in diabetes.
3Department of Histology and Cell Biology,
Faculty of Medicine, Minia University, El‐Minia,
Egypt
4Department of Pharmacology, Faculty of
Medicine, Minia University, El‐Minia, Egypt
5Institute of Organic Chemistry, Karlsruhe
Institute of Technology, Karlsruhe, Germany
6Institute of Biological and Chemical Systems,
Karlsruhe Institute of Technology,
Hermann‐von‐Helmholtz‐Platz 1,
Eggenstein‐Leopoldshafen, Germany
7Department of Chemistry, University of
Helsinki, Helsinki 00014, Helsinki,
A. I. Virtasen aukio I, Finland
K E Y W O R D S
8Department of Pharmaceutical Organic
Chemistry, Faculty Pharmacy, Al‐Azahr
University, Assiut Branch, Assiut, Egypt
4‐substituted hydrazinecarbothioamides, antihyperglycemic activity, bis(2‐(phenylsulfonyl)‐
ethyl)sulfane, glutathione, malondialdehyde, sulfonylalkylthiosemicarbazide
Correspondence
Ashraf A. Aly, Department of Chemistry,
Faculty of Science, Minia University,
El‐Minia 61511, Egypt.
Email: ashrafaly63@yahoo.com and
ashraf.shehata@minia.edu.eg
reaction conditions.[10,11] N‐Substituted hydrazinecarbothioamides are
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1
INTRODUCTION
considered as one of the most important classes of compounds con-
Due to the significant impact of sulfone compounds in biological appli-
cations, the development of new sulfone‐containing compounds remains
one of the central challenges of organic chemistry.[1,2] There are many
sulfones widely reported in the literature with a broad spectrum
of biological activities such as anticancer,[3] antimicrobial,[4] anti‐
inflammatory,[5] antiproliferative,[6,7] antimalarial[8] and anti‐HIV activ-
ities.[9] Catalytic chemoselective addition of amino alcohols to α,β‐
unsaturated sulfonyl derivatives leads to the regioselective formation of
amino and hydroxy adducts, depending on different catalysts and
taining nitrogen, sulfur, and oxygen used for heterocyclization and for-
mation of different heterocyclic rings such as thiadiazole and
thiadiazepine, and from the reaction with several π‐deficient com-
pounds.[12–15] The literature approach was applied to 4‐(1‐phenyl‐1H‐
tetrazole‐5‐ylsulfonyl)butanenitrile (PTSB), a growth inhibitory com-
pound with a previously unknown mode of action, and the thioredoxin/
thioredoxin reductase system was identified as its target.[16] Another
patent showed compounds having CH2CH2SO2Ar functional group as
histone deacetylase inhibitors.[17–18] The synthesis of various heterocyclic
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Arch Pharm. 2021;354:e2000336.
wileyonlinelibrary.com/journal/ardp
© 2021 Deutsche Pharmazeutische Gesellschaft
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rings, for example, pyrazoles, triazole thione, and thiadiazoles, can be
obtained via reaction of N‐substituted hydrazinecarbothioamides with
both 2‐bis(methylthio)methylene)malononitrile and ethyl 2‐cyano‐3,3‐bis
(methylthio)‐acrylate.[19] In light of our general aim to screen compounds
of biological and pharmaceutical importance, we designed, synthesized,
and screened a large variety of biologically active compounds.[20–27]
The total number of people with diabetes has been projected to
increase from 171 million in 2000 to 366 million by 2030. Diabetes
mellitus (DM) is managed by insulin and oral administration of hypogly-
cemic drugs such as sulfonylureas and biguanides.[28] DM is divided into
three main types: type I, type II, and gestational diabetes. Type II diabetes
mellitus (T2DM) accounts for more than 90% of all diabetic cases.[29]
T2DM is a heterogeneous disease associated with both genetic and en-
vironmental causative factors including multiple defects in insulin se-
cretion and action.[30,31] Insulin is a hormone that moves glucose inside
the cells to produce energy. Upon inadequate insulin secretion, the glu-
cose level in the blood increases (hyperglycemia). An extended period of
hyperglycemia causes irreversible damage to the eyes, kidneys, nerves,
and heart.[32] Hyperglycemia can be controlled by the administration of
insulin, which suppresses glucose production and augments glucose uti-
lization. Major classes of drugs used in the treatment of DM are insulins,
sulfonylureas, thiazolidinediones, biguanides, meglitinides, α‐glucosidase
inhibitors, dipeptidyl peptidase‐4 inhibitors, glucagon‐like peptide‐
1 agonists, sodium‐glucose cotransporter 2 inhibitors, and dopamine
agonists.[33] Sulfonylurea agents act by increasing insulin from β islet cells,
whereas biguanides act by reducing the excessive hepatic glucose pro-
duction. Tolbutamide (1, Figure 1) was the first‐generation sulphonylurea
drug developed, which was later surpassed by the second‐generation
gliclazide, glipizide, and glibenclamide (glyburide), and the third‐
generation agent glimepiride (2, Figure 1).[34] However, these agents are
associated with severe and sometimes fatal hypoglycemia, gastric dis-
turbances like nausea, vomiting, heartburn, anorexia, and increased ap-
petite.[35,36] Nevertheless, these hypoglycemic agents are actively
pursued, as it is very difficult to maintain normoglycemia by any means in
patients with DM. Therefore, the discovery of new hypoglycemic scaf-
folds with minimum side effects is still a challenge to medicinal
chemists.[37–39]
development of oxidative stress in diabetes has not been univocally
determined. A factor probably of greatest significance is hyperglycemia
occurring with hypoinsulinemia.[45] The lack of insulin leads to insulin‐
dependent disturbances in glucose metabolism, which is accompanied by
an increase in the autooxidation of glucose. During this process, the
reduction of the oxygen molecule and the generation of free radicals
occur. Insulin substitution causes a decrease in lipid peroxidation, an
increase in the activity of antioxidative systems, and normalization of
glucose levels.[45,46]
Although many examples of sulfonyl(thio)ureas are known, there
has been a limited investigation concerning separation by an alkyl
linker. However, a recent patent (US 2013‐14108597) offers a first
insight into the successful combination for the treatment of DM.
In this study, we disclose the reactivity of N‐substituted
hydrazinecarbothioamides 3a–d toward active sulfonyl compound,
(vinylsulfonyl)benzene (4) via the Michael addition reaction. The nu-
cleophilic addition between 3a–d and 4 affords different Michael ad-
ducts, depending on various active sites on hydrazinocarbothioamides.
Most indicative is to design compounds having a combination of two
structures, with both being bioactive scaffolds; one contains the
PhSO2CH2CH2 moiety and the other contains variable RNHCSNHNH
groups as bioactive scaffolds (Figure 2). The application of sulfonylalk-
ylthiosemicarbazide as antihperglycemic agents is not common.
Herein, we report a facile way for the preparation of sulfonylalk-
ylthiosemicarbazides and we test and screen their antihyperglycemic
activity using streptozotocin‐induced diabetic mice, blood glucose level,
and antioxidative enzyme activity. Also, a histological study of the pan-
creas is performed, compared with glimepiride.
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2
RESULTS AND DISCUSSION
Chemistry
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2.1
An equimolar mixture of hydrazinecarbothioamides 3a–d and
(vinylsulfonyl)benzene (4) was refluxed in absolute ethanol containing
catalytic amount of triethylamine, Et3N (0.5 ml), for 3–4 h, which
It is also perceived that in the case of diabetes, an increase of re-
active oxides and peroxides of lipids occurs along with the lower activity
of antioxidative factors.[40–44] The mechanism that is responsible for the
afforded
N‐substituted‐2‐(2‐(phenylsulfonyl)ethyl)hydrazinecarbothio‐
amides 5a–d, N2,N5‐diphenyl‐1,3,4‐thiadiazole‐2,5‐diamine (6a), and bis
(2‐(phenylsulfonyl)ethyl)sulfane (7) (Scheme 1). The reaction conditions
FIGURE 1 Chemical structures of some
sulfonylurea drugs

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from compound 12. Finally, bis(2‐(phenylsulfonyl)ethyl)sulfane 7[48] was
obtained via reaction of (vinylsulfonyl)benzene (4) with H2S. It is well
known that all the conjugate additions with vinyl sulfones share a similar
reaction pattern by addition at the β‐position of the sulfone. Hence, these
reactions are a well‐established method of creating β‐heterosubstituted
sulfones. In all cases, the resulting 1,4‐addition products contain either
the sulfonyl moiety, which can undergo subsequent functional group
transformations or can be easily removed, making these compounds a
perfect choice to afford easily naked alkyls.[49] Therefore, the extruded
H2S would add to 4 to give the zwitter ion D (Scheme 3), which would be
neutralized into the thiol compound E. The addition of E to another
molecule of 4 would form 7 (Scheme 3). The structures of compounds 6a
and 7 were confirmed via single‐crystal X‐ray structure analyses
(Figures 3 and 4).
FIGURE 2 Design of the target compounds 5a–d
(i.e., temperature, solvent, and/or catalyst) play an important role in the
reaction efficiency and product obtained; thus, different temperatures
and solvents such as dimethylformamide, ethyl acetate (EtOAc), and
tetrahydrofuran were used. Also, the use of catalytic amounts with few
drops of triethylamine or piperidine as inexpensive catalysts at room
temperature or refluxing temperature resulted in low yields and impure
products. However, the use of absolute ethanol and a few drops of
triethylamine while refluxing was the most efficient condition to get high
yields.
The molecular structure of the obtained compounds 5a–d was
confirmed on the basis of their mass spectrometric, infrared (IR), 1H
NMR (nuclear magnetic resonance), 13C NMR, two‐dimensional (2D)
NMR data (Section 4). As an example, the structure of compound 5b
(Figure 5) and its NMR spectroscopic data showed that H‐1a is dis-
tinctive at δH = 4.02; its attached carbon appears at δC = 51.66. H‐1a
gives COSY correlation with NH‐1, with the 2H signal at δH = 1.82 and
with the 4H signal at δH = 1.25. Each of these proton signals gives het-
eronuclear single quantum correlation (HSQC) with carbon at δC = 32.08.
The signal at δH = 1.82 is assigned as one pair of the nonequivalent
H‐1b, 2H signal at δH = 1.25 is assigned as the other pair of H‐1b, and the
The nucleophilic addition of N‐substituted hydrazinecarbothio-
amides 3a–d to vinylsulfonyl‐benzene (4) gave N‐substituted‐2‐(2‐
(phenylsulfonyl)ethyl)hydrazinecarbothioamides 5a–d instead of the
expected cyclized product (Z)‐N‐(5‐(phenylsulfonyl)‐1,3,4‐thiadiazinan‐2‐
ylidene)‐substituted amines 9a–d, which would be obtained via
intermediate 8a–d (Scheme 2).
carbon at δC = 32.08 is assigned as C‐1b. The other 2H signal at δH
=
1.25 and the 2H signal at δH = 1.68 are assigned as the two pairs of H‐1c;
their attached carbon appears at δC = 24.68. The 1H signals at δH = 1.57
and 1.12 are assigned as the nonequivalent H‐1d; their attached carbon
appears at δC = 25.11 ppm. Besides, in the case of compound 5d
(Figure 5) as an example, the IR spectrum showed absorptions at
ν = 3318, 3200, 3050, 2973, 1362, and 1592 cm–1 due to NHs, Ar‐CH,
Ali‐CH, C═S, and Ar‐C═C, respectively. NMR spectroscopic data
showed a 3H triplet in 1H NMR at δH = 1.05, assigned as H‐1b, and the
attached carbon appears at δC = 14.58. H‐1b gives COSY correlation and
The formation of the products 6a and 7 may be discussed via tau-
tomerism between thione and thiol of 3a–d, which was followed by the
formation of the salt A. Elimination of a molecule of hydrazine from A
would form an isothiocyanate intermediate (Scheme 3). Nucleophilic at-
tack of the hydrazinyl‐N lone pair of 3a on thiocarbonyl of isothiocyanate
intermediate would give B, and then another nucleophilic attack of thione
lone pair on the thiocarbonyl carbon would give C. N2,N5‐Diphenyl‐1,3,4‐
thiadiazol‐2,5‐diamine (6a)[47] was obtained via eliminating H2S molecule
SCHEME 1 The reaction between N‐substituted hydrazinecarbothioamides 3a–d and (vinylsulfonyl)benzene 4

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SCHEME 2 The Michael addition of N‐
substituted hydrazinecarbothioamides 3a–d to
(vinylsulfonyl)benzene 4
SCHEME 3 The mechanism for the formation of compounds 6a and 7
C‐1b gives heteronuclear multiple bond correlation (HMBC), with the
downfield part of the 4H envelope between δH = 3.44 and 3.42, assigned
as H‐1a; this envelope gives HSQC with carbon at δC = 37.68, which also
gives HMBC with H‐1b, so this carbon is assigned as C‐1a (Figure 5).
H‐1b gives HMBC with nitrogen (N‐1) at δN = 115.3, N‐1 gives HSQC
with its attached proton at δH = 7.89, and HMBC with another NH
proton at δH = 8.76, assigned as N‐3. N‐3 gives HSQC with its attached
nitrogen at δN = 134.6 and HMBC with the 2H “quartet” (H‐4a) at
these groups as compared with the diabetic group. However, MDA,
GSH, and blood glucose significantly increased in the diabetic group
as compared with the control group (Table 1).
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2.2.2
Hematoxylin and eosin stain (H&E) results
Pancreatic sections from the control group showed a normal lobular
structure. The pancreatic tissue showed both pancreatic acini and
islets of Langerhans. The pancreatic acini appeared with basal ba-
sophilia and apical acidophilia. The islet of Langerhans, pale areas
between acini, showed cells with vesicular nuclei and intercellular
blood vessels. Regarding the diabetic group, massive lobular distor-
tion and dilated blood vessels were noticed. Most of the pancreatic
acini displayed dense nucleoli. Other acini showed apoptotic nuclei.
δH = 2.92. H‐4a gives HMBC with carbon at δC = 180.64, assigned as
C‐2, and with the upfield half of the envelope between δH = 3.44 and
3.42, assigned as H‐4b. The phenyl signals are assigned straightfor-
wardly (Section 4). Elemental analysis and mass spectrometry
confirmed the formation of Michael adduct from the presence of
molecular ion peak at 287 [M+, 100], corresponding to the molecular
formula of C11H17N3O2S2.
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2.2
Biology
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2.2.1
Oxidative stress parameters
(malondialdehyde [MDA] and reduced glutathione
[GSH]) and blood glucose
The results with the new compound 5 showed a significant decrease
in MDA and blood glucose in all treated groups, compared with
the diabetic group. Moreover, GSH was significantly normalized in
FIGURE 3 The molecular structure of compound 6a
(displacement parameters are drawn at 50% probability level)

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2.3
Molecular docking
The KATP channels in pancreatic β cells indirectly sense blood glucose
concentration and gate insulin release. When blood glucose concentra-
tion is elevated, the ATP concentration inside β cells also increases due
to the active glucose uptake and metabolism. ATP can directly bind and
inhibit KATP, thereby leading to the depolarization of β cell plasma
membrane and activation of voltage‐gated calcium channels. Calcium
influx triggers insulin release from β cells.[53] The closure of pancreatic
KATP channels is integral to insulin secretion, and sulfonylureas, which
inhibit KATP channels, are widely used to treat type II diabetes. To ra-
tionalize the remarkable effect of the synthesized analogs, molecular
modeling and visualization processes were carried out with the referred
site of pancreatic ATP‐sensitive potassium channel obtained from the
Protein Data Bank (PDB code: 5WUA) using Molecular Operating
Environment (MOE®) version 2014.09. In this study, we docked all
derivatives, 5a–d, and glimepiride, as a reference, to predict the binding
interactions between the newly synthesized hydrazinecarbothioamide
sulfones and this site that is known to be involved in ligand binding and
enzymatic catalysis. The theoretical predictions from the molecular
docking study were found to agree with some highly active derivatives
such as 5b and 5d with the antihyperglycemic activity. All derivatives
were successfully docked, and the binding free energies from the major
docked poses are listed in Table 2 and the most favorable 2D poses of
the tested compounds are shown in (Figure 9). Scoring function (S score)
is used to approximately predict the binding affinity between ligand and
protein receptor. Most of the tested compounds have a high binding
affinity to the enzyme, as their binding free energy (ΔG) values range
from −0.6 to −2.4 kcal/mol, comparable to the reference
glimepiride (ΔG = −0.8 to −1.4 kcal/mol).
FIGURE 4 The molecular structure of compound 7 (displacement
parameters are drawn at 50% probability level)
FIGURE 5 The distinctive structures of compounds 5b and 5d
Degenerated islets of Langerhans and the inflammatory cell in-
filtration were frequently detected (Figures 6 and 7).
In the current work, diabetes resulted in severe distortion of the
islets with an apparent decrease in their cellularity. These findings
[50]
were in agreement with those of previous researchers
who re-
vealed the presence of shrunken islets with hydropic degeneration of
the cytoplasm in the diabetic pancreas. It was reported that the
damaging effects of DM on islet β cells were mediated via the in-
hibition of free radical scavenger enzyme, resulting in activation of
the production of superoxide, which is implicated in lipid oxidation,
DNA damage, and sulfhydryl oxidation, leading to degranulation and
loss of capacity to secrete insulin.[51]
The docking result of the reference compound glimepiride is com-
pletely consistent with the mode of action of hydrazinecarbothioamide
sulfones derivatives 5a–d. Stabilization of the reference compound gli-
mepiride within the active site occurred through two hydrogen bond
Also, there was a marked degeneration of the pancreatic acini
with loss of its basal basophilic and apical acidophilic portions. The
mechanism of degeneration of the exocrine parenchyma in DM was
attributed to the loss of high levels of insulin that perfuse the acini,
resulting in a trophic effect.[52] Both 5b and 5d showed amelioration
of lobular architecture. The islet of Langerhans appeared with more
numerous vesicular cells. Most pancreatic acini restored their basal
basophilic and apical acidophilic portions. 5a and 5c exhibited more
or less normal pancreatic tissue and normal pancreatic architecture,
and almost all pancreatic acini appeared with basal basophilia and
apical acidophilia. In most sections, invisible dilated blood vessels
were observed (Figures 6 and 7).
TABLE 1 Oxidative stress parameters MDA, GSH, and blood
glucose
Blood glucose
(mg/dl)
MDA (nmol/g
tissue)
GSH (mmol/g
tissue)
Groups
Control
5a
95 2.9
103.3 1.8a
256.7 8.8ab
102.3 3.9a
195 19ab
1.212 0.039
10.440 0.273ab
3.750 0.303ab
3.038 0.404ab
1.552 0.0189a
3.394 0.314ab
30.640 0.254b
0.433 0.033
0.633 0.033ab
0.567 0.033a
0.633 0.033ab
0.600 0.010ab
0.725 0.022ab
3.167 0.033b
5b
5c
5d
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2.2.3
Morphometric analysis
Glimipride 101.1 2.9ab
520 15b
There was a highly significant decrease in the mean diameter of islets
in the diabetic group if compared with the control one. However,
there was a significant increase in this parameter in 5a and 5d if
compared with the diabetic groups. Additionally, there was a low
significance difference between drugs 5a and 5c if compared with
drugs 5b and 5d (Figure 8).
Diabetic
Note: Values are a representation of observations as means SEM.
Results are considered significantly different when p < .05.
Abbreviations: GSH, reduced gluathione; MDA, malondialdehyde.
aSignificant difference compared with the diabetic group.
bSignificant difference compared with control.

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FIGURE 6 Photomicrographs of pancreatic sections revealed the control pancreatic tissue showing a normal lobular structure (L). The
diabetic group showed a marked lobular distortion (D) and dilated blood vessels (BV). 5b and 5d showed amelioration of lobular architecture
(L) with less dilated BV and amelioration of lobular architecture. 5a and 5c showed more or less normal pancreatic tissue (hematoxylin and
eosin stain ×100)
interactions with amino acid residue Phe 1496 (Figure 9). Docking results
with pancreatic KATP channel enzyme revealed that most of the tested
compounds show good binding and form several interactions, compar-
able to that of the reference compound glimepiride. Compound 5a
(Figure 9) exhibited two H‐bonding interactions with Pro 1429 and hy-
drophobic interaction with Leu 1431. Moreover, compound 5b showed
two hydrogen bonds with Ala 1493 and Arg 1494, and two hydrophobic
bonds with Ile 1457 and Ala 1527 (Figure 9). However, compound 5c
(Figure 9) formed two hydrogen bonds with the amino acid residues Thr
1450 and Arg 1494. Compound 5d formed two hydrogen bonds with
Arg 1494 and Tyr 512 (Figure 9).
antidiabetic agents with sulfonylurea‐like activity. The essential
moieties for activity are the thiosemicarbazide and phenylsulfonyl. In
addition, the extra N atom in thiosemicarbazide offers an additional
site for H‐bond formation with the protein that improves fitting,
compared with sulfonylureas. Moreover, the separation between
phenylsulfonyl and thiosemcarbazide moieties with ethyl group did
not reduce activity. The effect of the thiosemicarbazide substituents
R
(phenyl, cyclohexyl, allyl, and ethyl) on the activity is not
significant.
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3
CONCLUSION
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2.4
Structure–activity relationship
New hydrazinocarbothioamides derivatives were synthesized in a sim-
ple chemical reaction, and the synthesized hydrazinocarbothioamides
were screened for their antihyperglycemic activity in streptozotocin‐
induced diabetic mice. Results showed a significant decrease in MDA
From the biological results and docking studies, it was concluded that
sulfonylalkylthiosemicarbazide could be introduced as a new class of

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FIGURE 7 Photomicrographs of pancreatic sections revealed the control pancreatic tissue showing islet of Langerhans (star) with vesicular
cells (arrow) and intercellular blood vessels. The pancreatic acini appeared with basal basophilia (blue arrow) and apical acidophilia (yellow
arrow). The diabetic group showed degenerated islet of Langerhans (rectangle) and the inflammatory cell infiltration (double arrow). The
pancreatic acini appeared with dense nucleoli (triangle). Others showed apoptotic nuclei (circle). 5b and 5d showed amelioration of acinar
architecture. Islet of Langerhans appeared with more numerous vesicular cells (star). Most acini restored their basal basophilia (blue arrow) and
apical acidophilia (yellow arrow). 5a and 5c showed more or less normal pancreatic tissue. Glimepiride showed islet of Langerhans appearing
with more cells than the previous group (square). Still, some acini exhibited with apoptotic cells (circle) and others showed degenerated acini
(star) (hematoxylin and eosin stain × 400)
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and blood glucose in all treated groups, compared with the diabetic
group. Moreover, GSH significantly increased in these groups, com-
pared with the diabetic group. The results confirmed by histopatholo-
gical studies revealed the ability of the synthesized compounds to
protect pancreatic cells from massive lobular distortion, dilated blood
vessels, degenerated islets of Langerhans, and the inflammatory cell
infiltration noticed in the diabetic group. Compounds 5a and 5c re-
vealed the most significant reduction in blood glucose, which reflects
the importance of the presence of an efficient π system in the side chain
of hydrazinocarbothioamides.
4
EXPERIMENTAL
Chemistry
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4.1
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4.1.1
General
Melting points (MPs) were recorded on a Gallenkamp melting point
apparatus (Gallenkamp) by using open capillaries and were uncorrected.
NMR data were recorded on a Bruker AM 400 spectrophotometer,
1H‐NMR (400 MHz), and 13C‐NMR (100 MHz). Chemical shifts were

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visualized with ultraviolet light. Elemental analyses for C, H, and N were
carried out with Elementar 306.
The InChI codes of the investigated compounds, together with
some biological activity data, are provided as Supporting
Information.
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4.1.2
Synthsis of compounds 3a–d
N‐Substituted hydrazinecarbothioamides 3a–d were prepared ac-
cording to literature procedures (3a,[54]3b,[55]3c,[56] and 3d[57]). Also,
phenylvinyl sulfone 4 was purchased from Fluka.
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4.1.3
Reaction of N‐substituted
FIGURE 8 All studied groups showed the mean diameter of islets in
ps. Results represent the mean SEM (n = 6). aSignificant difference from
hydrazinecarbothioamides 3a–d and phenylvinyl
sulfone (4)
b
the control group, significant difference from the diabetic group, and
csignificant difference from 5a (p < 0.05)
The N‐substituted‐2‐[2‐(phenylsulfonyl)ethyl]hydrazineca‐rbothioamides
5a–d were synthesized via refluxing different solutions of the
N‐substituted hydrazinecarbothioamides 3a–d (1 mmol) and 4 in dry
EtOH containing 0.5 ml of triethylamine for 3–4 h. The reaction was
monitored by TLC, showing the total consumption of the starting
materials. The resulting mixtures were subjected to PLC (plate layer
chromatography) where two zones are separated using toluene/EtOAc
(10:5) as an eluent. The slowest zone contained 5a–d, whereas com-
pound 7 was obtained as the highest zone for all substituents of 3a–d.
Also, in the case of 3a, another product 6a was obtained as colorless
crystals during recrystallization from ethanol.
reported in ppm from tetramethylsilane using solvent resonance in
CDCl3 or deuterated dimethyl sulfoxide (DMSO‐d6) solutions as the
internal standard; s = singlet, t = triplet, q = quartet, m = multiplet, br =
broad. The 13C‐NMR signals were assigned on the basis of DEPT
135/90 spectra. The mass spectra were obtained on a Finnigan MAT
312 instrument using electron impact ionization (70 eV). The IR spectra
were recorded on a Bruker Alpha FT‐IR instrument with samples pre-
pared as potassium bromide pellets. Thin‐layer chromatography (TLC)
was performed on precoated plates (silica gel 60 PF254), and zones were
TABLE 2 Energy scores for the complexes formed by the tested
compounds 5a–d and the reference glimepiride in the active site of
pancreatic KATP channels (PDB: 5WUA)
N‐Phenyl‐2‐[2‐(phenylsulfonyl)ethyl]hydrazinecarbothioamide (5a)
Yield: 0.268 g (80%); colorless crystals (EtOH); MP: 87–88°C. IR
(KBr): ν = 3300, 3246 (NHs), 3105 (Ar‐H), 2922 (Ali‐CH), 1368 (C═S),
and 1593 (Ar‐C═C) cm−1 1H NMR (400 MHz, DMSO‐d6): δ = 2.95
.
ΔG
(kcal/
Ligand–receptor interaction
(q, 2H, CH2, J = 6.6), 3.40 (m, 2H, CH2N), 5.05 (s, 1H, 4NH), 7.06
(m, 3H, Ar‐H), 7.32 (m, 3H, Ar‐H), 7.71 (m, 2H, Ar‐H), 7.82 (m, 2H,
Ar‐H), 8.01 (s, 1H, 1NH), and 9.10 ppm (s, 1H, 3NH). 13C NMR
(100 MHz, DMSO‐d6): δ = 47.31 (CH2N), 56.00 (CH2–SO2), 125.3,
126.72, 128.17, 129.50, 131.00, 133.22 (Ar‐CH), 139.26, 139.66
(Ar‐C), and 181.00 (C═S) ppm. MS: m/z (70 eV, %) = 335 [M+, 51], 194
(10), 155 (30), 154 (100). 136 (72), 107 (21), and 77 (17). Anal. calcd.
for C15H17N3O2S2 (335.44); C, 53.71; H, 5.11; N, 12.53; S, 19.12.
Found: C, 53.77; H, 5.19; N, 12.45; S, 19.22.
Compound S score mol)a
Residue
Type
Length (Å)
Glimepiride −7.38
−1.4
−0.8
−1.5
−2.4
−0.8
−0.9
−0.9
−0.7
−0.6
−0.9
−0.7
−0.8
−0.9
Phe 1496 H‐donor
3.36
Phe 1496 H‐acceptor 3.10
5a
5b
−6.10
−6.01
Pro 1429 H‐donor
Pro 1429 H‐donor
Leu 1431 Pi–H
3.17
3.05
3.99
2.76
Ala 1493 H‐donor
Arg 1494 H‐acceptor 3.94
N‐Cyclohexyl‐2‐[2‐(phenylsulfonyl)ethyl]hydrazinecarbothioamide
(5b)
Ile 1457
Pi–H
3.95
4.00
3.13
Ala 1527 Pi–H
Yield: 0.256 g (75%); colorless crystals (EtOH); MP: 171–172°C. IR
(KBr): ν = 3320, 3250 (NHs), 3077 (Ar‐H), 2940 (Ali‐CH), 1368 (C═S),
and 1593 (Ar‐C═C) cm−1. NMR (DMSO‐d6): 1.12 (bt, J = 10 Hz, 1H,
H‐1d), 1.25 (m, 4H, H‐1b,1c), 1.57 (bd, J = 12 Hz; 1H, H‐1d), 1.68
(m, 2H, H‐1c), 1.82 (m, 2H, H‐1b), 2.93 (dt, Jd = 5.0; Jt = 6.6 Hz; 2H,
H‐4a), 3.39 (t, J = 6.7; 2H, H‐4b), 4.02 (m, 1H, H‐1a), 5.12 (t,
J = 4.1 Hz; 1H, H‐4), 7.69 (s, 1H, NH‐1), 7.70 (t, J = 7.6 Hz; 2H, H‐m),
5c
5d
−5.63
−5.56
Thr 1450 H‐donor
Arg 1494 H‐acceptor 4.01
Arg 1494 H‐donor
Tyr 512 H‐donor
3.00
4.16
aThe binding free energies.

ALY ET AL.
9 of 13
|
FIGURE 9 Two‐dimensional diagrams illustrating the binding modes of the reference glimepiride and 5a–d interaction with the active site of
pancreatic KATP channels

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ALY ET AL.
|
7.79 (tt, J = 7.4,1.5 Hz; 1H, H‐p), 7.90 (dd, J = 7.2;1.4 Hz; 2H, H‐o), and
8.75 (s; 1H, NH‐3). 13C NMR (100 MHz, DMSO‐d6): δ = 24.68, 25.11,
32.08, 44.18, 51.66, 52.91, 127.79, 129.57, 133.96, 139.09, and 179.71.
15N NMR (40 MHz, DMSO‐d6): δ = 69.5, 125.7, and 134.6 ppm. MS: m/z
(70 eV, %) = 341 [M+, 100], 200 (17), 185 (11), 154 (31), and 115 (45).
Anal. calcd. for C15H23N3O2S2 (341.49): C, 52.76; H, 6.79; N, 12.30; S,
18.78. Found: C, 52.69; H, 6.84; N, 12.23; S, 18.82.
on a Bruker D8 Venture diffractometer with a Photon II CPAD de-
tector at 123 K using Cu‐Kα radiation (λ = 1.54178 Å). Dual‐Space
Methods (SHELXT)[59] for 6a and 7 were used for structure solution
and refinement was carried out using SHELXL‐2014 (full‐matrix
least‐squares on F2)[60] for 6a and 7. Hydrogen atoms were refined
using a riding model (H [N] free). Semiempirical absorption correc-
tions were applied.
CCDC 1886120 (6a, M. Nieger, A. A. Aly, S. Bräse, CSD Com-
munication, 2018) and CCDC 1968395 (7) contain the Supporting
Information Crystallographic Data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data request/cif.
N‐Allyl‐2‐[2‐(phenylsulfonyl)ethyl]hydrazinecarbothioamide (5c)
Yield: 0.218 g (73%); colorless crystals (EtOH); MP: 82–83°C. IR
(KBr): ν = 3355, 3294 (NHs), 3100 (Ar‐H), 2919 (Ali‐CH), 1350 (C═S),
and 1596 (Ar‐C═C) cm–1 1H NMR (400 MHz, DMSO‐d6): δ = 2.93 (q,
.
2H, J = 6.5 Hz; CH2), 3.42 (m, 2H, CH2–SO2), 4.08 (m, 2H, CH2N), 5.09
(m, 2H, CH2═CH), 5.81 (m, 1H, CH2═CH), 5.13 (s, 1H, 4NH), 7.69 (t,
2H, J = 7.5 Hz; Ar‐H), 7.78 (t, 1H, J = 7.3 Hz; Ar‐H), 7.96 (s, 1H, 1NH),
7.88 (d, 2H, J = 7.6 Hz; Ar‐H), and 8.83 ppm (s, 1H, 3NH). 13C NMR
(100 MHz, DMSO‐d6): δ = 45.35 (CH2N), 44.24 (CH2‐allyl), 53.12
(CH2–SO2), 115.35 (CH2═CH), 127.52, 129.57, 134.00 (Ar‐CH),
135.18 (CH2═CH), 139.04 (Ar‐C), and 180.73 (C═S) ppm. MS: m/z
(70 eV, %) = 299 [M+, 100], 200 (17), 185 (11), 154 (31), and 115 (45).
Anal. calcd. for C12H17N3O2S2 (299.41): C, 48.09; H, 5.67; N, 14.03;
S, 21.37. Found: C, 48.16; H, 5.75; N, 13.96; S, 21.30.
Compound 6a
C14H12N4S, Mr = 268.34 g mol−1
, yellow crystals, size 0.16 × 0.16 ×
0.04 mm, monoclinic, space group Pc (no. 7), a = 11.0926 (5) Å, b = 7.0662
(3) Å, c = 8.5212 (4) Å, β = 104.429 (2) Å, V = 646.85 (5) Å3, Z = 2,
D
calcd = 1.378 Mg m−3, F(000) = 280, μ = 2.14 mm−1, Τ = 123 K, 8154
measured reflections (2θmax = 144.2°), 2397 independent reflections
(Rint = 0.024), 178 parameters, 4 restraints, R1 (for 2362 > 2σ [I]) = 0.033,
wR2 (for all data) = 0.087, S = 1.05, largest diff. peak and hole = 0.30 e
Å−3/−0.18 e Å−3. The absolute structure was determined by the refine-
ment of Flack's x‐parameter x = −0.01(2).[61] Compound 6a is a re-
determination of HAHGUT/HAHGUT01 (CSD refcode) at 123 K using
Cu‐Kα radiation. For HAHGUT, see CCDC‐237483 at lit[62] and for
HAHGUT01, see CCDC‐1020639, please see lit.[63]
N‐Ethyl‐2‐[2‐(phenylsulfonyl)ethyl]hydrazinecarbothioamide (5d)
Yield: 0.209 g (70%); colorless crystals (EtOH); MP: 148–149°C. IR
(KBr): ν = 3318, 3200 (NHs), 3050 (Ar‐H), 2973 (Ali‐CH), 1362 (C═S),
and 1592 (Ar‐C═C) cm−1 1H NMR (400 MHz, DMSO‐d6): δ = 1.05
.
(t, J = 7.0 Hz; 3H, H‐1b), 2.92 (q, J = 6.4 Hz; 2H, H‐4a), 3.42 (m; 2H,
H‐4b), 3.44 (m; 2H, H‐1a), 5.08 (s; 1H, H‐4), 7.70 (t, J = 7.4 Hz; 1H,
H‐m), 7.79 (t, J = 7.2 Hz; 1H, H‐p), 7.89 (s; 1H, NH‐1), 7.90
(d, J = 7.6 Hz; 2H, H‐o), and 8.76 (s; 1H, NH‐3). 13C NMR (100 MHz,
DMSO‐d6): δ = 14.58, 37.68, 44.25, 53.10, 127.55, 129.59, 133.99,
139.05, and 180.64. 15N NMR(40 MHz, DMSO‐d6): δ = 70.0, 115.3,
and 134.6 ppm. MS: m/z (70 eV, %) = 287 [M+, 100], 257 (13), 200
(25), 185 (10), 146 (9), and 103 (6). Anal. calcd. for C11H17N3O2S2
(287.40): C, 45.92; H, 5.91; N, 14.61; S, 22.26. Found: C, 46.01; H,
5.99; N, 14.69; S, 22.33.
Compound 7
C16H18O4S3, Mr = 370.48 g mol−1
, colorless crystals, size 0.16 ×
0.06 × 0.02 mm, monoclinic, space group P21/c (no. 14), a = 12.1183
(3) Å, b = 5.2041 (1) Å, c = 26.5839 (7) Å, β = 101.814 (1)Å,
V = 1641.00 (7) Å3, Z = 4, Dcalcd = 1.500 Mg m−3
,
F(000) = 776,
μ = 4.28 mm−1, Τ = 123 K, 15,972 measured reflections (2θmax = 144.2°),
3233 independent reflections (Rint = 0.033), 208 parameters, R1 (for
2954
>
2σ [I]) = 0.036, wR2 (for all data) = 0.091, S = 1.10,
largest diff. peak and hole = 0.50 e Å−3/−0.46 e Å−3
.
|
N2,N5‐Diphenyl‐1,3,4‐thiadiazole‐2,5‐diamine (6a)
Yield: 0.026 g (10%); colorless crystals.[58]
4.2
Pharmacological/biological assays
|
4.2.1
Animal experiments, ethical approval
Bis[2‐(phenylsulfonyl)ethyl]sulfane (7)
Yield: 0.019 g (7%); colorless crystals (EtOH); MP: 120–121°C [lit:
MP: 115–116°C].[41] 13C NMR (101 MHz, DMSO‐d6): δ = 23.86
(CH2), 54.64 (CH2), 127.73, 129.44, 133.86 (Ar‐CH), and 138.73
(Ar‐C).
Minia University Faculty of Medicine Research Ethics Committee
“BFMREC” approved this study proposal regarding the source of the
animals, health status, inclusion criteria, exclusion criteria, caging,
comfort, and the detailed experimental design and procedures. It was
conducted in agreement with the NIH Guide for Care and Use of
Laboratory Animals.
|
4.1.4
Single‐crystal X‐ray structure
Adult male Wistar albino rats weighing about 250–300 g were
purchased from the Animal Research Centre, Giza, Egypt. Rats were left
in standard housing conditions (three rats/cage) and were left to ac-
climatize for 1 week. Animals were supplied with laboratory chow and
tap water. Rats were randomly divided into seven groups (n = 6 each).
determination of 6a and 7
Single crystals of 6a and 7 were obtained by recrystallization from
EtOH. The single‐crystal X‐ray structure analyses were carried out

ALY ET AL.
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|
Statistical analysis
1. Control group rats were given an intraperitoneal injection of
0.5 ml/kg citrate buffer saline as a vehicle twice weekly for
14 days.
4.2.6
Results were expressed as means standard error of the mean.[70]
One‐way analysis of variance, followed by the Tukey–Kramer post‐
analysis test, was used to analyze the results, and p values less
than 0.05 were considered significant. GraphPad Prism was used
for statistical calculations (version 3.02 for Windows, GraphPad
Software, www.graphpad.com).
2. Diabetic group: Rats received a single intraperitoneal injection of
50 mg/kg STZ for induction of diabetes,[64] the other five
groups were treated with compounds 5a–d and glimipride as a
reference drug.
3. After 14 days, each rat was weighed and then killed. Venous blood
was collected from the jugular vein and centrifuged at 5000 rpm for
15 min (JanetzkiT30 centrifuge). After sacrifice, the pancreas was
excised and weighed. Parts of the pancreas was taken then fixed in
10% formalin and embedded in paraffin for histopathological ex-
aminations. The remaining parts were snap‐frozen in liquid nitrogen
and kept at −80°C. Pancreatic tissue homogenates were prepared
for biochemical analysis (Glas‐Col homogenizer). Pancreas homo-
genate was centrifuged at 3000 rpm for 20 min and the supernatant
was kept at −80°C until used.
|
4.3
Molecular docking
A docking simulation study was performed using the Molecular
Operating Environment (MOE®) version 2014.09, Chemical Com-
puting Group Inc. The target compounds were constructed into a 3D
model using the builder interface of the MOE program. After
checking their structures and the formal charges on atoms by the 2D
depiction, the following steps were carried out:
|
4.2.2
Evaluation of pancreatic tissue MDA and
1. All conformers were subjected to energy minimization; all the
minimizations were performed with MOE until a root mean
square deviation (RMSD) gradient of 0.01 kcal/mol and RMS dis-
tance of 0.1 Å with MMFF94X force field, and the partial charges
were automatically calculated.
reduced GSH[65]
MDA was detected depending on a reaction with the thiobarbituric
acid. The colored complexes were evaluated spectrophotometrically
at 535 nm and calculated using the standard curve of 1,1,3,
3‐tetramethoxypropane.[66] The GSH determination method was
based on the reduction of Ellman's reagent by the thiol groups of
GSH to produce a yellow color, which was measured spectro-
photometrically at 412 nm.[67]
2. The obtained data base was then saved as a Molecular Data Base
(MDB) file to be used in the docking calculations.
|
4.3.1
Optimization of the target
The X‐ray crystallographic structure of the target KATP channel
(PDB: 5WUA) was obtained from the Protein Data Bank. The com-
pounds were docked on the active site of the target enzyme.
The enzyme was prepared for docking studies by the following
methodology:
|
4.2.3
Histopathology study
Fresh small pieces of pancreatic tissue were obtained from each rat
and rapidly fixed in 10% neutral‐buffered formalin, dehydrated in a
graded alcohol series, cleared with xylene, and embedded in paraffin
wax. Sections (5 μm thick) were stained with H&E for studying the
general histological structure.[68]
1. The cocrystallized ligand was deleted.
2. Hydrogen atoms were added to the system with their standard
geometry.
3. The atoms' connection and type were checked for any errors with
automatic corrections.
|
4.2.4
Photography
4. The selection of the receptor and its atoms potential were fixed.
An Olympus (U.TV0.5XC‐3) light microscope and digital camera were
used in this current study. Images were performed using Adobe
Photoshop.
|
4.3.2
Docking of the target molecules to KATP
channel active site
|
4.2.5
Morphometric study
Docking of the target compounds was done using MOE‐Dock soft-
ware. The following methodology was generally applied:
The mean diameter of the islets of Langerhans was measured in this
study. Measurement of the average islet core diameter and exclusion
of the extension areas were carried out. This was performed using
power × 400 from 10 successive nonoverlapping fields.[69]
The enzyme active site file was loaded and the Dock tool was
initiated. The program specifications were adjusted to the following:
• Dummy atoms as the docking site.

12 of 13
ALY ET AL.
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• Triangle matcher as the placement methodology to be used.
• London dG as scoring methodology to be used, which was
adjusted to its default values.
[18] W. Ma, Y. Xie, X. Liao, J. Huang, W. Lin, Z. Long, AU 2018100066,
A4 20180215, 2018.
[19] A. A. Aly, A. A. Hassan, N. K. Mohamed, K. M. El‐Shaieb,
M. M. Makhlouf, S. Bräse, M. Nieger, Res. Chem. Intermed. 2019, 45,
613. https://doi.org/10.1007/s11164-018-3633-4
1. The MDB file of the ligand to be docked was loaded, and Dock
calculations were run automatically.
[20] E. M. El‐Sheref, A. A. Aly, A.‐F. E. Mourad, A. B. Brown, S. Bräse,
M. E. M. Bakheet, Chem. Pap. 2018, 72, 181. https://doi.org/10.
1007/s11696-017-0269-6
2. The obtained poses were studied, and the poses that showed the best
ligand–enzyme interactions were selected and stored for energy
calculations.
[21] A. A. Aly, E. M. El‐Sheref, A.‐F. E. Mourad, A. B. Brown, S. Bräse,
M. E. M. Bakheet, M. Nieger, Monatsh. Chem. 2018, 149, 635.
https://doi.org/10.1007/s00706-017-2078-6
[22] A. A. Aly, E. M. El‐Sheref, A.‐F. E. Mourad, M. E. M. Bakheet,
S. Bräse, M. Nieger, Chem. Pap. 2019, 73, 27. https://doi.org/10.
1007/s11696-018-0561-0
ACKNOWLEDGMENT
The authors thank the DFG Foundation for providing
a
[23] A. A. Aly, M. Ramadan, A. A. M. El‐Reedy, J. Heterocycl. Chem. 2019,
56, 642. https://doi.org/10.1002/jhet.3442
2‐month fellowship to Prof. Ashraf A. Aly, enabling him to carry out
the analysis of the compounds in the Karlsruhe Institute of
Technology, Karlsruhe, Germany, in July–August 2019.
[24] A. A. Aly, E. M. El‐Sheref, M. E. M. Bakheet, A.‐F. E. Mourad,
S. Bräse, M. A. A. Ibrahim, M. Nieger, B. K. Garvalov, K. N. Dalby,
T. S. Kaoud, Biorg. Chem. 2019, 82, 290. https://doi.org/10.1016/j.
bioorg.2018.10.044
ORCID
[25] A. A. Aly, E. M. El‐Sheref, M. E. M. Bakheet, A.‐F. E. Mourad,
A. B. Brown, S. Bräse, M. Nieger, M. A. A. Ibrahim, Bioorg. Chem.
2018, 81, 700. https://doi.org/10.1016/j.bioorg.2018.09.017
[26] A. A. Aly, E. M. El‐Sheref, A.‐F. E. Mourad, M. E. M. Bakheet,
S. Bräse, Mol. Divers. 2020, 24, 477. https://doi.org/10.1007/
s11030-019-09952-5.
Ashraf A. Aly
Marwa M. M. Refaie
Stefan Bräse https://orcid.org/0000-0003-4845-3191
https://orcid.org/0000-0002-0314-3408
http://orcid.org/0000-0001-6211-9558
Mohamed Ramadan
https://orcid.org/0000-0002-7975-3421
[27] M. A. I. Elbastawesy, A. A. Aly, M. Ramadan, Y. A. M. M. Elshaier,
B. G. M. Youssif, A. B. Brown, G. E.‐D. A. Abuo‐Rahma, Bioorg. Chem.
2019, 90, 103045. https://doi.org/10.1016/j.bioorg.2019.103045
[28] G. Gilman, L. S. Goodman, The Pharmacological Basis of Therapeutics,
5th ed., Macmillan, New York 1985.
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How to cite this article: Aly AA, Hassan AA, Makhlouf MM,
et al. Design and synthesis of hydrazinecarbothioamide sulfones
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