Synthesis and anti-hyperglycemic evaluation of novel carboximidamides derived from cyanamides

Article abstract of DOI:10.1016/j.molstruc.2021.129888

Carboximidamides 4-10 and 4,5-dihydro-1H-imidazol-2-amines 11, 12 linked with pyrimidine moiety were obtained via reaction of N-(pyrimidin-2-yl)cyanamides 1-3 with amines such as; morpholine, piperidine, piperazines and/or ethylenediamine, respectively. N-(4,6-Dimethylpyrimidin-2-yl)morpholine-4-carboximidamide 4 is subjected to react with 4-methylbenzenesulphonyl-, benzoyl-, and/or terephthaloyl chloride to give the corresponding N-substituted carboximidamides 13-16. The structure of new compounds was confirmed by using FT-IR and NMR spectral data. X-ray single crystal diffraction analysis of 15 revealed that the structure belongs to the monoclinic system and has a chair conformation in a morpholine ring. DMSO and carboximidamides 6, 8 caused a significant decrease in the serum level of glucose, comparing with the diabetic-treated group (streptozotocin-treated group). Furthermore they restored the serum levels of ALT, AST, triglyceride and cholesterol (Biomarker of liver function) to the levels similar or slightly higher than of the negative control group. Also, the biomarkers of kidney function (serum urea and creatinine) were restored to the level urea or slightly higher than their negative control on the administration of DMSO and carboximidamides 6, 8. So it can be concluded that, DMSO and carboximidamides 6, 8 may be used as ameliorative agents against streptozotocin-induced a pathological effects on blood glucose, liver function and kidney function. Morever, it can be stated that these compounds may be more effective in reducing the pathological effects of streptozotocin-induced diabetes than that of metformin.

Full text of DOI:10.1016/j.molstruc.2021.129888

Journal of Molecular Structure 1230 (2021) 129888
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Synthesis and anti-hyperglycemic evaluation of novel
carboximidamides derived from cyanamides
Amr H. Moustafaa,∗, Walaa W. Ahmeda, Ahmed Khodairya, Ahmed F. Mabiedb,c,d
Ahmed Moustafae, Mohamed F. El-Sayedf
,
a Department of Chemistry, Faculty of Science, Sohag University, Sohag 82524, Egypt
b X-Ray Crystallography Lab., Solid State Physics Department, National Research Centre, Dokki, Giza, Egypt
c Department of Basic Sciences, October High Institute of Engineering & Technology - OHI, 2ndNeighbourhood, 3rdDistrict, 6th of October, Giza, Egypt
d Egyptian National Committee of Crystallography, Academy of Scientific Research & Technology (ASRT), 101kasr Al-Aini St, Cairo, Egypt
e Faculty of Medicine, Sohag University, Sohag 82524, Egypt
f Department of Zoology, Faculty of Science, Sohag University, Sohag 82524, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
Carboximidamides 4-10 and 4,5-dihydro-1H-imidazol-2-amines 11, 12 linked with pyrimidine moiety
were obtained via reaction of N-(pyrimidin-2-yl)cyanamides 1-3 with amines such as; morpholine,
piperidine, piperazines and/or ethylenediamine, respectively. N-(4,6-Dimethylpyrimidin-2-yl)morpholine-
4-carboximidamide 4 is subjected to react with 4-methylbenzenesulphonyl-, benzoyl-, and/or tereph-
thaloyl chloride to give the corresponding N-substituted carboximidamides 13-16. The structure of new
compounds was confirmed by using FT-IR and NMR spectral data. X-ray single crystal diffraction analy-
sis of 15 revealed that the structure belongs to the monoclinic system and has a chair conformation in
a morpholine ring. DMSO and carboximidamides 6, 8 caused a significant decrease in the serum level
of glucose, comparing with the diabetic-treated group (streptozotocin-treated group). Furthermore they
restored the serum levels of ALT, AST, triglyceride and cholesterol (Biomarker of liver function) to the
levels similar or slightly higher than of the negative control group. Also, the biomarkers of kidney func-
tion (serum urea and creatinine) were restored to the level urea or slightly higher than their negative
control on the administration of DMSO and carboximidamides 6, 8. So it can be concluded that, DMSO
and carboximidamides 6, 8 may be used as ameliorative agents against streptozotocin-induced a patho-
logical effects on blood glucose, liver function and kidney function. Morever, it can be stated that these
compounds may be more effective in reducing the pathological effects of streptozotocin-induced diabetes
than that of metformin.
Received 14 October 2019
Revised 3 December 2020
Accepted 5 January 2021
Available online 7 January 2021
Keywords:
Carboximidamide
Cyanamides
Diabetic
Anti-hyperglycemic
Pyrimidine
Structure crystallographic analysis
© 2021 Elsevier B.V. All rights reserved.
1. Introduction
buformin have since been discontinued during the 1970s [6] and
therefore metformin (rarely causes lactic acidosis) was remained
Type 2 diabetes mellitus (T2DM) is a disease that is character-
ized by raised blood glucose levels and it accounts for at least 90%
of all cases of diabetes [1,2]. For this purpose, two groups of oral
anti-hyperglycemic drugs such as sulphonyl ureas and biguanides
have been used in the treatment of T2DM [3]. In spite of the
worse outcomes of most sulfonylureas, the newer agents do not
appear to increase the risk of death, heart attacks or strokes [4].
The biguanides such as phenformin, buformin and metformin were
first discovered in the 1950s, (Fig. 1) [5]. But as a result of the
lactic acidosis that is associated with the use of phenformin and
the only biguanide that is available for commercial use to treat-
ment T2MD [7,8].
Carboximidamides have been previously prepared [9–16] and
they exhibit pharmacological activities such as; antihypoglycemic
[17], Tuberculostatic, antimicrobial [15,18,19], antileishmanial
[20] antidegenerative [21], antitumor [22], anti-HIV [23] and
antiplatelet [24]. Their derivatives were evaluated in vitro as
dual COXs/LOX inhibitors [16] and as a pre-clinical development
candidate for the treatment of migraine [25] and Melanoma [26].
There are several synthetic routes were schemed for prepa-
ration of carboximidamide derivatives via: (i) The reaction of
ammonia/HCl(g)
, sulphonamides, or aliphatic/aromatic amines
∗
Corresponding author.
with substrates containing nitrile group [10,12,18–20]; (ii) The
reaction of carboximidoyl chlorides with aliphatic/aromatic
E-mail addresses: amr_hassanegypt@ymail.com,
amr_hassanegypt@science.sohag.edu.eg (A.H. Moustafa).
https://doi.org/10.1016/j.molstruc.2021.129888
0022-2860/© 2021 Elsevier B.V. All rights reserved.

A.H. Moustafa, W.W. Ahmed, A. Khodairy et al.
Journal of Molecular Structure 1230 (2021) 129888
Scheme 1. Synthesis of carboximidamides 4-10 and 4,5-dihydro-1H-imidazol-2-amines 11, 12. Reagents and conditions: (a) sec. amines: morpholine or piperidine, H2O, r.t.,
12 hrs.; (b) 1-(4-methoxyphenyl)piperazine, iso-PrOH, reflux, 8 hrs; (c) piperazine, iso-PrOH, reflux, 8 hrs.; (d) ethylenediamine, dioxane, reflux, 7 hrs.
Scheme 2. Synthesis of morpholine-4-carboximidamides 13-16. Reagents and conditions: (a) 4-methylbenzenesulphonyl chloride, TEA, dry dioxane, 80 °C, 7 hrs.; (b,c) acid
chlorides: benzoyl chloride, 2,4-dichlorobenzoyl chloride or terephthaloyl chloride, TEA, dry dioxane, r.t., 7 hrs.
amines [27]; (iii) The reaction of aminoguanidine with ketones
[28], β-diketones [29], enones [13] or pyrimidines [30]; (iv)
The reaction of aryl amidoximes with compounds containing
carboxylic group [9,16,31]; (v) One-pot three-component reac-
tion of o-aminobenzhydrazide, 2-pyridine/pyrazinecarbonitrile
and aromatic aldehydes [32]; (vi) One-pot Cu-catalyzed mul-
Undoubtedly, cyanamide derivatives having both imino (NH)
and cyano (CN) groups can undergo reactions with various nucle-
ophilic and/or electrophilic reagents [36–40]. These findings moti-
vated us in the present work to design and synthesize new car-
boximidamides 4-10 and 4,5-dihydro-1H-imidazol-2-amines 11,12
via reaction of cyanamides with different aliphatic amines using
various solvents: water, iso-propanol and/or dioxane, (Scheme 1).
The greatest advantage in this preparation method is that, all
new obtained products having pyrimidinyl moiety in their struc-
tures linked directly with the target carboximidamide fragment,
and they can undergo another substitution using different elec-
ticomponent
reaction
of
benzylamine/aniline
derivatives,
trichloroacetonitrile, phenylacetylene and sodium azide [11];
(vii) Three-component reaction of carbodiimides, isocyanides,
and trimethylsilyl azide [33]; (viii) Other miscellaneous methods
[14,34,35].
2

A.H. Moustafa, W.W. Ahmed, A. Khodairy et al.
Journal of Molecular Structure 1230 (2021) 129888
Table 1
X-ray Diffraction details of compound 15.
Compound 15
Crystal data
Chemical formula
Mr
C18H19Cl2N5O2
408.29
Crystal system, space group
Temperature (K)
Monoclinic, P21/n
298
˚
a, b, c (A)
10.8590 (7), 15.5100 (8), 11.6550 (8)
β (°)
97.570 (3)
3
˚
V (A )
1945.9 (2)
Z
4
Radiation type
Mo Kα
μ (mm−1
)
0.36
Fig. 1. Sulphonylureas and biguanides agents.
Crystal size (mm)
0.49 × 0.40 × 0.30
Refinement
R[F2 > 2σ(F2)], wR(F2), S
No. of reflections
No. of parameters
H-atom treatment
0.047, 0.072, 1.00
1049
244
H-atom parameters constrained
0.37, -0.32
−3
˚
ꢀρmax, ꢀρmin (e A
)
analyses, (see Experimental and Supplementary Material). IR
spectra of compounds 4-12 showed the absence of characteris-
≡
tic absorption band corresponding to C N group and appeared
Fig. 2. Formation of hydrogen bond for compounds 14-16.
new bands for N-H group and C-H aliphatic. Their 1H NMR
spectra showed new signals corresponding to NH, methylene
aliphatic protons in aliphatic region and other signals char-
acteristic for each one. While 13C NMR spectra showed new
trophiles. Thus the obtained carboximidamide 4 is subjected to
react with benzoyl-, 4-methylbenzenesulphonyl- and/or tereph-
thaloyl chloride, (Scheme 2). During our research into new antidi-
abetic agents, the new two carboximidamides 6,8 of the highest
hypoglycemic effect were selected using online PASS Inet [41] and
screened in vivo in mice as anti-hyperglycemic activity. More-
over, single crystal X-ray studies were performed to identify the
molecular structure of the prepared compounds, and they pro-
vided us the essential chemical information such as; stereochem-
istry, bond distances, angles and packing of the molecules in the
crystal [42].
CH2 groups at
2-yl)morpholine-4-carboximidamide (4) was reacted with
4-methylbenzenesulfonyl chloride, benzoyl chloride, 2,4-
δ 24.7-66.4 ppm. N-(4,6-Dimethylpyrimidin-
dichlorobenzoyl chloride and/or terephthaloyl chloride in dry diox-
ane in the presence of triethylamine (TEA) to give the correspond-
ing N-[4-methylbenzenesulfonyl]-N’-(4,6-dimethylpyrimidin-2-yl)
morpholine-4-carboximidamide (13), N-[(4,6-dimethylpyrimidin-
2-ylamino)(morpholin-4-yl)methylidene]benzamide
(14),
2,4-
dichloro-N-[(4,6-dimethylpyrimidin-2-ylamino)(morpholin-4-yl)
methylidene]benzamide (15) and N,N’-bis-[(4,6-dimethylpyrimidin-
2-ylamino)(morpholin-4-yl)methylidene]terephthalamide
(Scheme 2).
(16),
2. Results and discussion
The structures of the newly carboximidamides 13-16 were con-
firmed based on their spectral (IR, 1H, 13C NMR) and elemental
analysis data, further confirmed by single-crystal X-ray crystallog-
raphy for 15 (see Experimental and Supplementary Material). IR
spectra of compounds 13-16 showed the absence of characteristic
absorption band corresponding to N-H group and appeared new
bands for C-H aromatic, while the characteristic bands for C=O and
initial NH groups in compounds 14-16 did not appear due to the
formation of intramolecular hydrogen bond (Fig. 2) as confirmed
by X-ray single crystal results, (see X-ray crystallography section,
Fig. 5). Their 1H NMR spectra showed new signals corresponding
to aromatic and methyl protons . Also 13C NMR spectra showed
the increasing of aromatic carbon signals.
2.1. Chemistry
The starting materials, N-(pyrimidin-2-yl)cyanamides 1-3
were prepared according to the methods that were previ-
ously reported [38,43,44]. In the present work, we succeeded
to synthesize some new carboximidamides 4-10 and 4,5-
dihydro-1H-imidazol-2-amines 11, 12, (Scheme 1). Reaction of
N-(pyrimidin-2-yl)cyanamides 1-3 with 2-fold molar excess
of sec. amines such as; morpholine and/or piperidine gave
the corresponding N-(substituted pyrimidin-2-yl)morpholine-
4-carboximidamides 4,
6 and/or N-(substituted pyrimidin-2-
yl)piperidine-4-carboximidamide 5, respectively. The reaction
was carried out at room temperature via nucleophilic addi-
tion of NH group at cyano cyanamide group in water as
a
protic solvent. While, reaction of cyanamides 2, 3 with each
of 1-(4-methoxyphenyl)piperazine as 1:1 molar ratio and/or
piperazine as 2:1 molar ratio was achieved by refluxing for 8
hrs in iso-propanol to give the corresponding N-(substituted
2.2. X-ray crystallography
The X-ray crystallographic analysis revealed that, the compound
15 crystallized in a monoclinic system with four molecules in
the unit cell, as given in Table 1. The molecular structure of the
compound 15 is depicted as ORTEP view with the atom num-
bering scheme in Fig. 3. The results showed that the structure
centered mainly on carboximidamide moiety linked with carbonyl
group, where N13 attached with 4,6-dimethylpyrimidine, C5 with
dichlorophenyl ring and the heterocyclic morpholine ring con-
nected to C10.
pyrimidin-2-yl)piperazine-1-carboximidamides 7,
8
and N1,N4-
bis(substituted pyrimidin-2-yl)piperazine-1,4-dicarboximidamides
9, 10, respectively. While, the reaction of compounds 2, 3 with
ethylenediamine as bidentate nucleophile, gave N-(4,5-dihydro-
1H-imidazol-2-yl)pyrimidin-2-amines 11 and 12, respectively,
(Scheme 1).
The structures of the newly synthesized compounds 4-12
were confirmed by their spectral IR, 1H-, 13C NMR and elemental
3

A.H. Moustafa, W.W. Ahmed, A. Khodairy et al.
Journal of Molecular Structure 1230 (2021) 129888
Fig. 3. A view of the structure of 15, showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level.
Fig. 4. A view of packing diagram shows the Cg-Cg interaction (dashed lines) of the title compound 15.
Planar configuration of the individual rings of the structure
ring puckered and suggested chair conformation, as shown in
was noticed, where the least-squares plane passing through N8-
C24—C18- C21-N17-C16 (4,6-dimethylpyrimidine ring) and C14-
C9-C7-C25-C11-C12 (dichlorophenyl ring) showed planar config-
Fig. 4 [45,46].
In the compound 15, the crystal packing formed networks
(Fig. 4), and no classic intermolecular hydrogen bonds were ob-
served. However, intra-hydrogen-bonding interactions were no-
ticed (Table 2). The crystal packing is further stabilized by a pi-
ring Cg (I)…Cg (J) stacking intermolecular interactions, where Cg
refers to the center of gravity of the ring, Cg(2) and Cg(3) refer
to the rings 4,6-dimethylpyrimidine and dichlorophenyl, respec-
˚
uration, with maximum deviation of -0.022(7) A for C14. How-
ever, morpholine ring revealed non planarity where O20 and N3
˚
˚
deviated 0.651(5) A and 0.603(1) A respectively from the plane
passing through the other constituent atoms (C19- C15- C22-
C27). Ring puckering and conformation analyses showed that the
4

A.H. Moustafa, W.W. Ahmed, A. Khodairy et al.
Journal of Molecular Structure 1230 (2021) 129888
Fig. 5. A view of the compound 15 structure showing the chair configuration and
H13..O6 intra hydrogen bond with dashed line (some hydrogen atoms are hidden
for best view).
Fig. 6. Effect of DMSO, compounds 6, 8 (as a single dose) and metformin on glu-
cose concentration (mg/dI) in the serum of albino rats (Rattus rattus).
Table 2
˚
Hydrogen-bond geometry (A, °) for the title compound 15.
D—H···A
D—H
H···A
D···A
D—H···A
N13—H13···O6
0.86
0.98
1.92
2.52
2.623 (10)
3.132 (10)
138
120
C19—H191···C16
˚
˚
tively. The distances 3.318(4) A for Cg(2)-Cg(2)i and 3.908(4) A
for Cg(3)…Cg(3)ii (symmetry codes i= -x,-y,-z and ii= -x,1-y,-z) h
(Fig. 4). No solvent molecules have been found in the crystal pack-
ing.
2.3. Biological activity
2.3.1. Blood glucose
Relative to the negative control, streptozotocin caused a highly
significant (p < 0.05) increase in the level blood glucose. But,
DMSO and compounds 6, 8 resulted in a highly significant (p <
0.05) decrease in the blood glucose level, in comparison with the
positive control group. Relative to the negative control, DMSO and
compounds 6, 8 resulted in a highly significant (p < 0.05) increase
in the blood glucose level (Fig. 6).
Fig. 7. Effect of DMSO, compounds 6, 8 (as repeated dose) and metformin on glu-
cose concentration (mg/dI) in the serum of albino rats (Rattusrattus).
The influence of injection of the above diabetic treated group
for another four days with DMSO, compounds 6, 8 (repeated
dose) and metformin for only one day on the blood glucose level
was also examined. Relative to the negative control, streptozotocin
(positive control), DMSO, compounds 6, 8 and metformin led to a
highly significant increase (p < 0.05) in the blood glucose level.
However, DMSO, compounds 6, 8 and metformin led to a highly
significant decrease (p < 0.05) in the blood glucose level, in com-
parison with positive control. But, the decreased in the blood glu-
cose level as a result of the effect of compound 8 was pronounced,
which reduced the blood glucose level to the third, as compared
with that of the positive control (Fig. 7).
of positive control was very highly significant increase than neg-
ative control. Also, the influence of DMSO on the serum level of
ALT was more pronounced. It caused a very highly significant (p <
0.05) decrease in the serum level of ALT than the positive control
and the other compounds 6, 8.
2.3.2.2. Serum aspartate transaminase (AST). As illustrated in Fig. 9,
streptozotocin (positive control), DMSO and compounds 6, 8 re-
sulted in a highly significant increase (p < 0.05) in the serum
level of AST, relative to the negative control. But, these treatments
(DMSO and compounds 6, 8) resulted in a very highly significant
(p < 0.05) decrease in the serum level of AST, relative to positive
control (streptozotocin).
2.3.2. Liver function
2.3.2.1. Serum ALT level. As indicated in Fig. 8, streptozotocin (pos-
itive control), DMSO and compounds 6, 8 caused a highly signif-
icant (p < 0.05) increase in serum level of ALT, relative to nega-
tive control. In comparison with positive control, DMSO and com-
pounds 6, 8 caused a highly significant (p < 0.05) decrease in the
serum level of ALT. It should be noted that, the serum level of ALT
2.3.2.3. Serum triglycerides. Streptozotocin led to a very highly sig-
nificant increase (p < 0.05) in the serum concentration of triglyc-
erides, in comparison with the negative control. Also, DMSO led to
5

A.H. Moustafa, W.W. Ahmed, A. Khodairy et al.
Journal of Molecular Structure 1230 (2021) 129888
Fig. 8. Effect of DMSO and compounds 6, 8 (as repeated dose) on ALT concentra-
tion(U/L) in the serum of albino rats (Rattusrattus).
Fig. 10. Effect of DMSO and compounds 6, 8 (as repeated dose) on triglyceride con-
centration in the serum of albino rats (Rattusrattus).
Fig. 9. Effect of DMSO and compounds 6, 8 (as repeated dose) on AST concentra-
tion(U/L) in the serum of albino rats (Rattusrattus).
Fig. 11. Effect of DMSO and compounds 6, 8 (as repeated dose) on cholesterol con-
centration (mg/dI) in the serum of albino rats (Rattusrattus).
a significant (p < 0.05) increase in the serum level of triglycerides,
while compounds 6, 8 led to a significant (p < 0.05) decrease in
the serum level of triglyceride, relative to that of the negative con-
trol. However, DMSO and compounds 6, 8 caused a very highly
significant (p < 0.05) decrease in the serum level of triglyceride,
relative to the positive control (Fig. 10).
that of the negative control. Also, DMSO and compounds 6, 8
caused a significant (p < 0.05) increase in the serum level of urea
relative to the negative control. However, DMSO and compounds 6,
8 resulted in a highly significant (p < 0.05) decrease in the serum
level of urea, relative to the positive control (Fig. 12).
2.3.2.4. Serum cholesterol. As illustrated in Fig. 11, streptozotocin,
DMSO and compounds 6, 8 resulted in a highly significant (p <
0.05) increase in the serum level of cholesterol relative to the neg-
ative control. Also, DMSO and compounds 6, 8 resulted in a highly
significant increase (p < 0.05) in the serum level of cholesterol rel-
ative to that of the positive control.
2.3.3.2. Serum creatinine. As indicated in Fig. 13, streptozotocin
(positive control) resulted in a very highly significant (p < 0.05)
increase in the serum level of creatinine, in comparison with that
of the negative control. But, DMSO and compounds 6, 8 resulted
in a significant (p < 0.05) increase in the serum level of creatinine,
relative to the negative control, also. On the other hand, DMSO and
compounds 6, 8 caused a highly significant (p < 0.05) decrease in
the creatinine level, in comparison with the positive control (strep-
tozotocin).
2.3.3. Kidney function
2.3.3.1. Serum urea level. Streptozotocin caused a very highly sig-
nificant increase in the serum concentration of urea, relative to
6

A.H. Moustafa, W.W. Ahmed, A. Khodairy et al.
Journal of Molecular Structure 1230 (2021) 129888
cholesterol which showed a significant increase under the effect
of the treatments used in the current study, relative to that of the
positive control.
4. Materials and methods
4.1. Chemistry
4.1.1. General information
All information about reagents, reactions, spectral apparatus:
FT-IR, 1H NMR, 13C NMR and elemental analyses were recorded in
Supporting Information.
4.1.2. General procedure for synthesis of compounds 4-6
A mixture of cyanamides 1, 2 (5 mmol) and secondary amines
namely: piperidine and/or morpholine (10 mmol) was stirred in
distilled water (50 mL) at room temperature for 12 hrs. The ob-
tained crude product was filtered, washed with distilled water,
dried and recrystallized from iso-propanol.
N-(4,6-Dimethylpyrimidin-2-yl)morpholine-4-
carboximidamide (4):
Yield 85 %; white solid; m.p.: 193-195°C. IR (ATR) νmax 3268,
3156, 3027, 2968, 2927, 2845, 1623 cm−1 1H NMR δ: 9.39 (br.
.
Fig. 12. Effect of DMSO and compounds 6, 8 (as repeated dose) on urea concentra-
tion (mg/dI) in the serum of albino rats (Rattusrattus).
s, 2H, 2NH), 7.01 (s, 1H, CHarom.), 3.69 (s, 4H, 2CH2), 3.63 (s, 4H,
2CH2), 2.42 (s, 6H, 2CH3). Anal. Calcd. for C11 H17 N5O (235.28): C,
56.15; H, 7.28; N, 29.77. Found: C, 56.03; H, 7.15; N, 29.62.
N-[4-(4-Methoxyphenyl)pyrimidin-2-yl]piperidine-1-
carboximidamide (5):
Yield 81 %; white solid; m.p.: 196°C. IR (ATR) νmax 3296, 3150,
3002, 2930, 2850, 1609 cm−1
.
1H NMR δ: 8.42, 8.41 (d, J = 2.8 Hz,
1H, CHpyrimidine), 8.30 (br. s, 2H, 2NH), 8.02, 8.00 (d, J = 7.8 Hz,
2H, CHarom.), 7.18, 7.17 (d, J = 2.8 Hz, 1H, CHpyrimidine), 7.07, 7.05 (d,
J = 7.8 Hz, 2H, CHarom.), 3.84 (s, 3H, OCH3), 3.59 (s, 4H, 2(CH2)-N),
1.62 (s, 2H, CH2), 1.54 (s, 4H, 2CH2). 13C NMR δ: 166.6, 163.1, 161.7,
158.0, 157.4, 130.1, 128.7, 114.6, 106.8, 55.8, 45.1, 26.0, 24.7. Anal.
Calcd. for C17 H21N5O (311.38): C, 65.57; H, 6.80; N, 22.49. Found:
C, 65.81; H, 6.64; N, 22.58.
N-[4-(4-Methoxyphenyl)pyrimidin-2-yl]morpholine-4-
carboximidamide (6):
Yield 83 %; beige solid; m.p.: 286-288°C. IR (ATR) νmax 3334,
.
3165, 3045, 2964, 2899, 2857, 1605 cm−1 1H NMR δ: 8.45, 8.44
(d, J = 5.0 Hz, 3H, CHpyrimidine + 2NH), 8.04, 8.02 (d, J = 8.4
Hz, 2H, CHarom.), 7.24, 7.23 (d, J = 5.0 Hz, 1H, CHpyrimidine), 7.07,
7.05 (d, J = 8.4 Hz, 2H, CHarom.), 3.83 (s, 3H, OCH3), 3.65-363
(m, 4H, 2CH2), 3.58-3.56 (m, 4H, 2CH2). 13C NMR δ: 166.4, 163.2,
161.7, 158.1, 157.8, 130.0, 128.7, 114.6, 107.3, 66.4, 55.8, 44.7. Anal.
Calcd. for C16 H19N5O2 (313.35): C, 61.33; H, 6.11; N, 22.35. Found:
C, 61.16; H, 6.32; N, 22.24.
Fig. 13. Effect of DMSO and compounds 6, 8 (as repeated dose) on creatinine con-
centration (mg/dI) in the serum of albino rats (Rattusrattus).
4.1.3. General procedure for synthesis of compounds 7 and 8
An equimolar amount of cyanamides 2, 3 (5 mmol) and 1-(4-
methoxyphenyl)piperazine (5 mmol, 0.96 g) was refluxed in iso-
propanol (50 mL) for about 8 hrs. After completion of reaction
(monitored by TLC), the reaction mixture was cooled to room tem-
perature and the product was filtered, washed with iso-propanol.
The products 7 and 8 were used without further purification.
4-(4-Methoxyphenyl)-N-[4-(4-methoxyphenyl)pyrimidin-2-
yl]piperazine-1-carboximidamide (7):
3. Conclusion
A
novel series of carboximidamides and 4,5-dihydro-1H-
imidazol-2-amines was synthesized by the reaction of N-
(pyrimidin-2-yl)cynamides with secondary amines and/or
ethylenediamine. The utility of N-(4,6-dimethylpyrimidin-2-
yl)morpholine-4-carboximidamide as building block for synthesis
Yield 82 %; beige solid; m.p.: 184°C. IR (ATR) νmax 3314, 3163,
.
3039, 2992, 2956, 2904, 2830, 1610 cm−1 1H NMR δ: 8.46, 8.45
a
novel class of N-acylated derivatives was also investigated.
It should be noted that streptozotocin, as expected resulted in
a highly significant increase in the blood glucose. Moreover, it
resulted in a highly increase in the serum level of ALT, AST,
urea, creatinine, triglyceride and cholesterol. On the other hand,
treatments by DMSO and compounds 6, 8 caused a highly signif-
icant decrease in the serum level of parameters examined, except
(d, J = 4.7 Hz, 2H, CHpyrimidine + NH), 8.05, 8.03 (d, J = 8.8 Hz, 2H,
CHarom.), 7.24, 7.22 (d, J = 5.1 Hz, 1H, CHpyrimidine), 7.08, 7.06 (d,
J = 8.8 Hz, 2H, CHarom.), 6.96, 6.94 (d, J = 9.0 Hz, 2H, CHarom.), 6.86,
6.83 (d, J = 9.0 Hz, 2H, CHarom.), 3.84 (s, 3H, OCH3), 3.77-3.75 (t,
J = 4.4 Hz, 4H, 2CH2), 3.70 (s, 3H, OCH3), 3.4 (br. s, 1H, NH), 3.08-
3.06 (t, J = 4.3 Hz, 4H, 2CH2). 13C NMR δ: 166.2, 163.2, 161.8, 158.1,
7

A.H. Moustafa, W.W. Ahmed, A. Khodairy et al.
Journal of Molecular Structure 1230 (2021) 129888
157.5, 153.7, 145.7, 129.9, 128.8, 118.3, 114.9, 114.7, 107.3, 55.8, 50.2,
44.4, 44.3. Anal. Calcd. for C23H26N6O2 (418.49): C, 66.01; H, 6.26;
N, 20.08. Found: C, 66.27; H, 6.18; N, 20.34.
161.6, 160.3, 139.2, 129.6, 128.8, 128.1, 112.6, 60.6, 42.1, 14.1. Anal.
Calcd. for C16 H17 N5O2 (311.33): C, 61.72; H, 5.50; N, 22.49. Found:
C, 61.55; H, 5.58; N, 22.38.
Ethyl 2-{[imino(4-(4-methoxyphenyl)piperazin-1-yl)methyl]
amino}-4-phenylpyrimidine-5-carboxylate (8):
4.1.6. General procedure for synthesis of compounds 13 - 16
A mixture of carboximidamide 4 (5 mmol, 1.18 g), triethylamine
(5 mmol, 0.7 mL) and 4-methylbenzenesulfonyl-, benzoyl-, 2,4-
dichlorobenzoyl chloride (5 mmol) and/or terephthaloyl chloride
(2.5 mmol, 0.5 g) was stirred in dry dioxane (50 mL) at room
temperature (except in case 4-methylbenzenesulphonyl chloride at
80°C) for about 7 hrs. After completion of reaction (monitored by
TLC), the reaction mixture was added into distilled water and the
formed product was filtered, washed with distilled water, dried
and recrystallized from ethanol.
Yield 79 %; white solid; m.p.: 174–176°C; IR (ATR) νmax 3312,
.
3178, 3043, 2974, 2890, 2820, 1723, 1622 cm−1 1H NMR δ: 8.83 (s,
1H, CHpyrimidine), 8.57 (br. s, 2H, 2NH), 7.49-7.43 (m, 5H, CHarom.),
6.97, 6.94 (d, J = 8.9 Hz, 2H, CHarom.), 6.86, 6.83 (d, J = 8.9 Hz, 2H,
CHarom.), 4.11-4.05 (q, J = 7.1 Hz, 2H, CH2CH3), 3.79-3.77 (t, J = 4.1
Hz, 4H, 2CH2), 3.70 (s, 3H, OCH3), 3.07-3.05 (t, J = 4.1 Hz, 4H,
2CH2), 1.06-1.02 (t, J = 7.1 Hz, 3H, CH3). 13C NMR δ: 166.9, 166.2,
166.0, 160.4, 158.1, 153.8, 145.6, 139.4, 129.7, 128.8, 128.3, 118.4,
114.7, 113.3, 60.8, 55.7, 50.2, 44.2, 14.1. Anal. Calcd. for C25H28N6O3
(460.52): C, 65.20; H, 6.13; N, 18.25. Found: C, 65.39; H, 6.34; N,
17.97.
N-[4-Methylbenzenesulfonyl]-N’-(4,6-dimethylpyrimidin-2-
yl)morpholine-4-carboximidamide (13):
Yield 74 %; beige solid; m.p.: 208–210°C. IR (ATR) νmax 3244,
3079, 3017, 2975, 2903, 2852, 1600, 1259 cm−1 1H NMR δ: 8.90
.
4.1.4. General procedure for synthesis of compounds 9 and 10
A mixture of cyanamides 2, 3 (5 mmol) and piperazine (2.5
mmol, 0.22 g) was refluxed in iso-propanol (50 mL) for about 8
hrs. After completion of reaction, the reaction mixture was cooled
to room temperature and the product was filtered, washed with
iso-propanol and recrystallized from iso-propanol - DMF.
N1,N4-Bis{[4-(4-methoxyphenyl)pyrimidin-2-yl]}piperazine-
1,4-bis-carboximidamide (9):
(br. s, 1H, NH), 7.53-7.51 (d, J = 7.5 Hz, 2H, CHarom.), 7.16-7.14
(d, J = 7.5 Hz, 2H, CHarom.), 6.76 (s, 1H, CHpyrimidine), 3.62 (s,
4H, 2CH2), 3.45 (s, 4H, 2CH2), 2.27 (s, 3H, CH3), 2.26 (s, 6H,
2CH3pyrimidine). 13C NMR δ: 168.2, 157.5, 153.0, 142.0, 141.1, 129.3,
126.4, 114.2, 65.9, 47.4, 23.6, 21.2. Anal. Calcd. for C18 H23N5O3S
(389.47): C, 55.51; H, 5.95; N, 17.98. Found: C, 55.59; H, 5.78; N,
17.78.
N-[(4,6-Dimethylpyrimidin-2-ylamino)(morpholin-4-
yl)methylidene]benzamide (14):
Yield 69 %; white solid; m.p.: 280–282°C. IR (ATR) νmax 3265,
.
3166, 3009, 2965, 2905, 1625 cm−1 1H NMR δ: 8.46 (s, 2H,
Yield 76 %; beige solid; m.p.: 150–152°C. IR (ATR) νmax 3055,
2CHpyrimidine), 8.37 (s, 4H, 4NH), 8.05, 8.03 (d, J = 6.5 Hz, 4H,
4CHarom.), 7.23 (s, 2H, 2CHpyrimidine), 7.08, 7.07 (d, J = 6.5 Hz, 4H,
4CHarom.), 3.86 (s, 6H, 2OCH3), 3.72 (s, 8H, 4CH2). 13C NMR δ:
166.4, 163.3, 161.8, 158.1, 157.6, 130.1, 128.7, 114.7, 107.3, 55.8, 43.9.
Anal. Calcd. for C28H30N10O2 (538.60): C, 62.44; H, 5.61; N, 26.01.
Found: C, 62.31; H, 5.37; N, 26.25.
2986, 2918, 2870, 1603 cm−1 1H NMR δ: 10.70 (s, 1H, NH), 8.03-
.
7.42 (m, 5H, CHarom.), 6.72 (s, 1H, CHpyrimidine), 3.73 (s, 4H, 2CH2),
3.65 (s, 4H, 2CH2), 2.17 (s, 6H, 2CH3). 13C NMR δ: 175.4, 168.0,
158.3, 154.4, 138.1, 131.7, 129.4, 128.2, 114.2, 66.3, 47.1, 23.5. Anal.
Calcd. for C18 H21N5O2 (339.39): C, 63.70; H, 6.24; N, 20.64. Found:
C, 63.99; H, 6.01; N, 20.59.
Diethyl
N1,N4-bis(carbonimidoylimino)piperazine-bis[(4-
2,4-Dichloro-N-[(4,6-dimethylpyrimidin-2-ylamino)
(morpholin-4-yl)methylidene]benzamide (15):
phenyl-pyrimidin-2-yl)-5-carboxylate] (10):
Yield 62 %; white solid; m.p.: 150–152°C. IR (ATR) νmax 3370,
.
3140, 3057, 2982, 2930, 1723, 1624 cm−1 1H NMR δ: 8.83 (s, 2H,
Yield 79 %; brown crystal; 152–154°C. IR (ATR) νmax 3019, 2959,
.
2924, 2842, 1602 cm−1 1H NMR δ: 10.46 (br. s, 1H, NH), 7.86 (s,
2CHpyrimidine), 8.56 (br. s, 4H, 4NH), 7.47 (s, 10H, CHarom.), 4.09
(s, 4H, 2CH2CH3), 3.74 (s, 8H, 4CH2piperazine), 1.04 (s, 6H, 2CH3).
13C NMR δ: 167.0, 166.2, 166.0, 160.3, 158.3, 139.5, 129.6, 128.7,
128.3, 113.5, 60.7, 43.7, 14.1. Anal. Calcd. for C32H34N10O4 (622.67):
C, 61.72; H, 5.50; N, 22.49. Found: C, 61.88; H, 5.45; N, 22.43.
1H, CHarom.), 7.53–7.43 (m, 2H, CHarom.), 6.74 (s, 1H, CHpyrimidine),
3.69 (s, 4H, 2CH2), 3.62 (s, 4H, 2CH2), 2.23 (s, 6H, 2CH3). 13C NMR
δ: 173.2, 167.9, 158.4, 154.5, 136.8, 135.0, 133.2, 133.0, 130.0, 127.1,
114.3, 66.3, 47.1, 23.6. Anal. Calcd. for C18 H19 Cl2N5O2 (408.28): C,
52.95; H, 4.69; N, 17.15. Found: C, 52.57; H, 4.71; N, 17.23.
N,N’-Bis-[(4,6-dimethylpyrimidin-2-ylamino)(morpholin-4-
yl)methylidene]terephthalamide (16):
4.1.5. General procedure for synthesis of compounds 11 and 12
A mixture of cyanamides 2, 3 (5 mmol) and ethylenediamine
(10 mmol, 0.68 mL) was refluxed in dioxane (50 mL) for about 7
hrs. After completion of reaction (monitored by TLC), the reaction
mixture was cooled to room temperature and the product was fil-
tered, washed with dioxane and recrystallized from iso-propanol.
N-(4,5-Dihydro-1H-imidazol-2-yl)-4-(4-methoxyphenyl)
pyrimidin-2-amine (11):
Yield 77 %; beige solid; m.p.: 258–260°C. IR (ATR) νmax 3055,
.
2972, 2916, 2850, 1607 cm−1 1H NMR δ: 10.68 (br. s, 2H, 2NH),
8.04 (s, 4H, CHarom.), 6.72 (s, 2H, 2CHpyrimidine), 3.73 (s, 8H, 4CH2),
3.65 (s, 8H, 4CH2), 2.16 (s, 12H, 4CH3). 13C NMR δ: 174.9, 168.0,
158.3, 154.7, 129.3, 128.9, 114.2, 66.8, 47.2, 23.5. Anal. Calcd. for
C30H36N10O4 (600.67): C, 59.99; H, 6.04; N, 23.32. Found: C, 60.31;
H, 6.14; N, 23.22.
Yield 62 %; beige solid; m.p.: 114–116°C. IR (ATR) νmax 3246,
.
3058, 2953, 2883, 2835, 1625 cm−1 1H NMR δ: 8.41-8.40 (d,
J
=
4.7 Hz, 1H, CHpyrimidine), 8.06, 8.04 (d,
J
=
8.1 Hz, 4H,
4.2. X-ray single crystal diffraction
2CHarom. + 2NH), 7.20, 7.18 (d, J = 4.7 Hz, 1H, CHpyrimidine), 7.07,
7.05 (d, J = 8.1 Hz, 2H, 2CHarom.), 3.84 (s, 3H, OCH3), 3.57 (s, 4H,
2CH2). 13C NMR δ: 166.9, 163.5, 163.2, 161.7, 158.1, 130.1, 128.8,
114.6, 107.2, 55.8, 42.0. Anal. Calcd. for C14 H15N5O (269.30): C,
62.44; H, 5.61; N, 26.01. Found: C, 62.17; H, 5.70; N, 26.16.
Ethyl 2-(4,5-dihydro-1H-imidazol-2-ylamino)-4-phenylpyri-
midine-5-carboxylate (12):
An appropriate crystal for single crystal X-ray study of com-
pound 15 has been selected, and mounted onto thin glass fibers.
X-Ray single crystal diffraction data were collected at room tem-
perature (298 K) on an Enraf-Nonius 590 diffractometer with
a
Kappa CCD detector using graphite monochromated Mo-Kα
˚
(λ = 0.71073A) radiation, at National Research Center, Egypt [47].
Reflection data has been recorded in the rotation mode using the
φ and ω scan technique with 2θmax = 33. In the absence of
significant anomalous scattering, Friedel pairs have been merged.
Changes in illuminated volume were kept to a minimum, and were
taken into account by the multi-scan inter-frame scaling [48,49].
Yield 56 %; beige solid; m.p.: 136–138°C. IR (ATR) νmax 3315,
.
3176, 3063, 2985, 2935, 2854, 1725, 1644 cm−1 1H NMR δ: 8.78,
8.69 (2 s, 1H, CHpyrimidine), 7.44 (s, 7H, 5CHarom. + 2NH), 4.08-4.02
(q, J = 7.0 Hz, 2H, CH2CH3), 3.57 (s, 2H, CH2), 3.30 (s, 2H, CH2),
1.04-1.00 (t, J = 7.0 Hz, 3H, CH3). 13C NMR δ: 168.5, 166.0, 164.1,
8

A.H. Moustafa, W.W. Ahmed, A. Khodairy et al.
Journal of Molecular Structure 1230 (2021) 129888
Unit cell parameters were determined from least-squares refine-
ment with θ in the range 2.910 ≤ θ ≤ 33. The structure of 15
was solved by direct methods using SHELX [50] implemented in
CRYSTALS program suit [51]. The refinement was carried out by
full-matrix least-squares method on the positional and anisotropic
temperature parameters of all non-hydrogen atoms based on F2 us-
ing CRYSTALS package [52]. All hydrogen atoms were positioned
geometrically and were initially refined with soft restraints on the
bond lengths and angles to regularize their geometry (C—H in the
range 0.93–0.98 and N—H in the range 0.86–0.89) and Uiso(H)
(in the range 1.2-1.5 times Ueq of the parent atom). Then, the
positions were refined with riding constraints [53]. The general-
purpose crystallographic tool PLATON [54] was used for the struc-
ture analysis and presentation of the results. The molecular graph-
ics were done using DIAMOND [55] program. Details of the data
collection conditions and the parameters of the refinement process
are given in Table 1.
4.3.4. Biochemical analysis
The activities of some biochemical parameters representing
liver and kidney functions were measured in the blood serum of
rats colorimetrically. The blood glucose concentration was mea-
sured using Caraway & Walts (1987) and Howantiz & Howantiz
(1984) methods [56,57]; An alanine aminotransferase (ALT) and
Aspartate Aminotransferase (AST) were measured using Bergmeyer
& Bernt (1974) methods [58,59] and serum triglycerides concen-
tration was measured according to the method of Bablock et al.,
(1988) [60]. For kidney function, Serum urea level was mea-
sured according to the methods of Kaplan (1984) and Tabacco
et al., (1979) [61,62]; and serum creatinine level was mea-
sured according to Bartles et al. (1972) and Cook (1971) methods
[63,64].
Declaration of Competing Interest
The full crystallographic information can be obtained free of
charge using deposit number CCDC 1582055, via http://www.ccdc.
cam.ac.uk/conts/retrieving.html or from the Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
(+44) 1223-336-033; or e-mail: deposit@ccdc.cam.ac.uk.
The authors declare that they have no conflict of interest.
CRediT authorship contribution statement
Amr H. Moustafa: Conceptualization, Formal analysis, Visual-
ization, Supervision, Writing - review & editing. Walaa W. Ahmed:
Methodology, Data curation, Funding acquisition. Ahmed Kho-
dairy: Project administration, Supervision, Writing - original draft,
Supervision. Ahmed F. Mabied: Software, Formal analysis, Writ-
ing - original draft. Ahmed Moustafa: Investigation, Methodology,
Supervision. Mohamed F. El-Sayed: Validation, Writing - original
draft, Resources.
4.3. Biological activity
4.3.1. Chemicals
Streptozotocin – induced diabetic drug and dimethyl sulphoxide
(DMSO) were obtained from Merck Company Germany. N-[4-(4-
Methoxyphenyl)pyrimidin-2-yl]morpholine-4-carboximidamide
6
and ethyl 2-{[imino(4-(4-methoxyphenyl)piperazin-1-yl)methyl]
amino}-4-phenylpyrimid-ine-5-carboxylate 8 were prepared in our
organic lab.
Acknowledgments
Zoology Department at Sohag University is highly acknowl-
edged for providing support regarding the biological facilities. Also
we thank Professor Aisha Moustafa, X-Ray Crystallography Lab.,
Physics Division, National Research Centre, Dokki, Cairo 12622,
Egypt, for his help and for providing the facilities during the X-Ray
crystallography determination.
4.3.2. Experimental animals
This study was carried out on 30 male albino rats (Rattus rattus)
approximately 8-10 weeks old, their weights ranging from 160-180
gm. The animals were obtained from the animal house of Zool-
ogy Department, Faculty of Science, Sohag University. They were
housed in stainless cages at room temperature, five rats each and
acclimatized to laboratory condition two weeks before the exper-
iment and fed commercial pallet rat food. Food and water were
available add libitum. Lightin221g cycle of 12 hours (light/dark) was
also in consideration.
Supplementary materials
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.molstruc.2021.129888.
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