Design, synthesis, DFT, molecular modelling studies and biological evaluation of novel 3-substituted (E)-5-(arylidene)-1-methyl-2-thioxoimidazolidin-4-ones with potent cytotoxic activities against breast MCF-7, liver HepG2, and lung A549

Article abstract of DOI:10.1016/j.molstruc.2020.129805

We report the synthesis of novel 3-substituted (E)-5-(arylidene)-1-methyl-2-thioxoimidazolidin-4-ones 6-11, and their biological evaluation. Based on structural and pharmacophore analyses of known inhibitors such as fluorouracil (5-FU), we envisioned interesting 2-thioxoimidazolidin-4-one compounds, 3-substituted (E)-5-(arylidene)-1-methyl-2-thioxoimidazolidin-4-ones 6-11 that would be expected to well match the structural features in 5-FU. Efficient synthesis of twenty-four target compounds 6-11 were achieved through the synthetic pathway of 5 → 6 → 7 → 10 → 11, established after consideration of several plausible synthetic pathways. A series of (E)-5-(arylidene)-1-methyl-2-thioxoimidazolidinoneones 5a-d were synthesized via the reaction of 1-methyl-2-thioxoimidazolidin-4-one (3), which in turn was prepared via the reaction of N-methyl glycine (2) with NH₄SCN, followed by Knoevenagel condensation. N-alkylation and N-glycosylation were carried via the reaction of 5a-d with alkyl bromides and α-glycopyranosyl bromides 9a,b under alkaline and glycoside conditions, respectively. The N-alkylated and N-glycosylated structures have been selected for the products. Conformational analysis has been studied by homonuclear and heteronuclear two-dimensional NMR methods (DQF-COSY, HMQC, and HMBC). The N site of alkylation and glycosylation were determined from the ¹H, ¹³C heteronuclear multiple-quantum coherence (HMQC) experiments. Molecular modelling and DFT calculations using B3LYP/6-31+G (d, p) level were performed to study the electronic and geometric properties obtained from the stable structure of the investigated compounds. A good correlation between the quantum chemical descriptors and experimental observations was found. The synthesized derivatives exhibited good binding interactions towards the cyclin-dependent kinase 2, especially compound 11b, which have better key interactions than the co-crystallized ligand. Additionally, it had potent cytotoxic activities with IC₅₀ = 4.30, 5.53, 9.43 against MCF-7, HepG2, and A549, respectively.

Full text of DOI:10.1016/j.molstruc.2020.129805

Journal of Molecular Structure 1229 (2021) 129805
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Design, synthesis, DFT, molecular modelling studies and biological
evaluation of novel 3-substituted
(E)-5-(arylidene)-1-methyl-2-thioxoimidazolidin-4-ones with potent
cytotoxic activities against breast MCF-7, liver HepG2, and lung A549
Ahmed I. Khodaira,∗, Safyah B. Bakareb, Mohamed K. Awad c, Mohamed S. Nafied
a Chemistry Department, Faculty of Science, Kafrelsheikh University, 33516 Kafrelsheikh, Egypt
b Faculty of Education, Shaqra University, Al Muzahimiyah, Shaqra, Riyadh Province, P.O. Box 90, Zip Code 11921, Kingdom Saudi Arabia
c Theoretical Applied Chemistry Unit (TACU), Chemistry Department, Faculty of Science, Tanta University, Tanta, Egypt
d Chemistry Department, Faculty of Science, Suez Canal University, 41522 Ismailia, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
We report the synthesis of novel 3-substituted (E)-5-(arylidene)-1-methyl-2-thioxoimidazolidin-4-ones
6-11, and their biological evaluation. Based on structural and pharmacophore analyses of known in-
hibitors such as fluorouracil (5-FU), we envisioned interesting 2-thioxoimidazolidin-4-one compounds, 3-
substituted (E)-5-(arylidene)-1-methyl-2-thioxoimidazolidin-4-ones 6-11 that would be expected to well
match the structural features in 5-FU. Efficient synthesis of twenty-four target compounds 6-11 were
achieved through the synthetic pathway of 5 → 6 → 7 → 10 → 11, established after consideration of
several plausible synthetic pathways. A series of (E)-5-(arylidene)-1-methyl-2-thioxoimidazolidinoneones
5a-d were synthesized via the reaction of 1-methyl-2-thioxoimidazolidin-4-one (3), which in turn was
prepared via the reaction of N-methyl glycine (2) with NH4SCN, followed by Knoevenagel condensa-
tion. N-alkylation and N-glycosylation were carried via the reaction of 5a-d with alkyl bromides and α-
glycopyranosyl bromides 9a,b under alkaline and glycoside conditions, respectively. The N-alkylated and
N-glycosylated structures have been selected for the products. Conformational analysis has been studied
by homonuclear and heteronuclear two-dimensional NMR methods (DQF-COSY, HMQC, and HMBC). The
N site of alkylation and glycosylation were determined from the 1H, 13 C heteronuclear multiple-quantum
coherence (HMQC) experiments. Molecular modelling and DFT calculations using B3LYP/6-31+G (d, p)
level were performed to study the electronic and geometric properties obtained from the stable structure
of the investigated compounds. A good correlation between the quantum chemical descriptors and exper-
imental observations was found. The synthesized derivatives exhibited good binding interactions towards
the cyclin-dependent kinase 2, especially compound 11b, which have better key interactions than the
co-crystallized ligand. Additionally, it had potent cytotoxic activities with IC50 = 4.30, 5.53, 9.43 against
MCF-7, HepG2, and A549, respectively.
Received 30 October 2020
Revised 16 December 2020
Accepted 21 December 2020
Available online 24 December 2020
Keywords:
N-Methyl glycine
(E)-5-(arylidene)-1-methyl-2-thio-4-
imidazolidineones
imidazolidine N-nucleosides, molecular
docking
MTT assay
apoptosis
quantum chemical descriptors, DFT
calculations
© 2020 Elsevier B.V. All rights reserved.
1. Introduction
pharmaceutical intermediates, and agrochemicals. As examples, the
isatinylidene derivative I (Fig. 1) exhibit immunosuppressive ac-
2-Thioxo-4-imidazolidinones were surveyed as biologically rele-
vant moieties against different cancer cell lines, so in the present
study, we analyzed novel derivatives as target-oriented chemother-
apeutic anticancer drugs. 2-Thioxo-4-imidazolidinone compounds
[1,2] and their 2-alkylthioxo-4-imidazolidinone derivatives are a
biologically important class of compounds in the fields of drugs,
tivity [3] and the thioglycosyl hydantoin [4] II possesses a broad-
spectrum antitumor activity against a wide range of different hu-
man cell lines from nine tumor subpanels causing both cyto-
static and cytotoxic effects. The 5-arylmethylene-2-methylthio-4-
imidazolidinones III substituted with a biphenyl tetrazole (BTP)
group at the C-2 position show activities as angiotensin II re-
ceptor antagonists [5] and the 3-morpholinomethyl-5,5-dimethyl-
2-thioglycosyl-4-imidazolidinone IV has been also identified as a
potential AZT analogue [6]. The 2-thioxo-4-imidazolidinone deriva-
tives have not only been used in medicinal chemistry but have
∗
Corresponding author.
E-mail address: khodair2020@yahoo.com (A.I. Khodair).
https://doi.org/10.1016/j.molstruc.2020.129805
0022-2860/© 2020 Elsevier B.V. All rights reserved.

A.I. Khodair, S.B. Bakare, M.K. Awad et al.
Journal of Molecular Structure 1229 (2021) 129805
Fig. 1. Select 4-imidazolone derivatives with biological activities.
also been developed as fungicides [7] [e. g., fenamidone (V) [8,9]
and herbicides [10]. Recent work [11] by Wang’s group has es-
tablished that esters of 5-(4-hydroxybenzyl)-2-thioxoimidazolidin-
4-ones exhibit good herbicidal activity against Zea mays and Ara-
bidopsis thaliana.
tions have become essential to elucidate structures, properties
of molecules, mechanisms, and selectivity of reactions [56]. The
density functional theory (DFT) is one of the most popular the-
oretical methods used in calculating a great variety of molecular
properties such as molecular structures, vibrational frequencies,
chemical shifts, non-linear optical (NLO) effects, natural bond
orbital (NBO) analysis, molecular electrostatic potential, frontier
molecular orbitals and thermodynamic properties [56-60]. The
present work aims to perform the density functional theory to
study the effect of the molecular and electronic structure changes
on the biological activity of the investigated compounds and try
to find a good correlation between the theoretical data with the
experimental observations.
On the other hand, the synthesis, and biological properties
of 2-alkylthio-5-arylidene-4-imidazolidinone derivatives VI has
rarely been the subject of detailed investigations reported in the
literature. A 25-year-old study of Unangst and co-workers only
reported the preparation of (5Z)-[(3,5-bis(1,1-dimethylethyl)-4-
hydroxyphenyl]methylene]-1,5-dihydro-1-methyl-2-methylthio-4H-
imidazol-4-one for an inflammation therapy program [12]. In 1993,
a report described the biological activity of the same compound
as a potent antiviral agent for the human immunodeficiency virus
(HIV) [13]. More recently, the use of 5-arylidene-1-methyl-1,5-
dihydro-4H-imidazol-4-one as a convenient synthetic intermediate
2. Results and Discussion
in
example [14,15]. As the first part of this study, we at this mo-
ment report the synthesis and spectroscopy of new series
a sulfur/nitrogen displacement has been studied with one
2.1. Chemistry
a
The synthetic pathway for the described compounds is il-
lustrated in Scheme 1. The synthesis started with the prepara-
tion of 1-methyl-2-thioxoimidazolidin-4-one (3) [61,72] by the fu-
sion of methyl amino acetic acid (1) with ammonium thiocyanate
at 140-150 °C through the formation of 1-(methylthioureido)-
acetic acid (2) as intermediate. Compound 3 was then condensed
with the appropriate aryl carboxaldehydes namely benzaldehyde
(4a), 4-methylbenzaldehyde (4b), 4-methoxybenzaldehyde (4c)
and finally 4-chlorobenzaldehyde (4d) to yield the correspond-
ing (E/Z)-5-(benzylidene)-1-methyl-2-thioxoimidazolidin-4-one 5a
(E/Z ratio, 1.3:1.0), respectively and (E)-5-(arylidene)-1-methyl-2-
thioxoimidazolidin-4-ones 5b-d (Scheme 1). The structures of com-
pounds 5a-d were established and confirmed by elemental anal-
yses and spectral data (IR, 1H-NMR, 13C-NMR, and MS). The IR
absorption spectra of 5a–d were characterized the presence of a
signal for NH group at vmax 3094-3230 cm−1 and the presence
of N-alkylated bearing 1-methal-2-thioxoimidazolidin-4-ones as
potential antiviral and antitumor activities (Schemes 1 and 2).
Moreover, nucleoside analogs constitute an important class of
therapeutic agents in the treatment of cancers and viral infections
[16,17]. The mode of action of these derivatives is based upon
their intracellular conversation to their phosphorylated forms
(nucleotides), which can interact with different cell biosynthesis.
During the last decades, intensive research was dedicated to
the discovery of more effective, selective, and non-toxic new
nucleoside derivatives [18-21]. Glycosides of structurally similar
heterocyclic systems have been reported before and in continua-
tion of our work on the synthesis of novel nucleosides as potential
antiviral, antitumor agents and keeping in mind the biological
significance of imidazolidin-2,4-diones, 2-thioxoimidazolidin-
4-ones,
2-thioxopyrimidin-4-ones,
2-thioxothiazolidin-4-ones,
2-thioxopyridines and 2-thioxoquinazolin-4-ones [22-55]. As the
second part of this study, we at this moment report the synthe-
sis and spectroscopy of a new series of N-glycosylated bearing
(E)-5-(arylidene)-1-methyl-2-thioxoimidazolidin-4-one bases as
potential antiviral and antitumor activities (Scheme 3). This is the
first time to prepare N-glycosides of (E)-5-(arylidene)-1-methyl-2-
thioxoimidazolidin-4-ones via new synthetic strategies. In the last
few decades, computational chemistry has progressed from a rarity
to become a full partner with an experiment in the investigation
of organic and biochemical structures and reactions. Computa-
of a signal for the thiocarbonyl group at vmax 1314-1386 cm−1
1H–NMR(500 MHz, DMSO-d6) spectrum of compound 5a (E-form)
.
showed a singlet at δH 3.47 ppm assigned to the methyl pro-
ꢀ
ton of N1-CH3, a multblet at δH 7.35-7.43 ppm assigned to 2 -H,
ꢀ
ꢀ
6’-H, 3 -H, 5’-H, a multblet at δH 7.82-8.02 ppm assigned to 4 -
H, a singlet at 6.63 ppm assigned to the =CH and a broad sin-
glet at δH 12.13 ppm assigned to NH. 1H–NMR(500 MHz, DMSO-
d6) spectrum of compound 5a (Z-form) showed a singlet at δH
3.20 ppm assigned to the methyl proton of N1-CH3, a multblet
ꢀ
ꢀ
at δH 7.35-7.43 ppm assigned to 2 -H, 6’-H, 3 -H, 5’-H, a mult-
2

A.I. Khodair, S.B. Bakare, M.K. Awad et al.
Journal of Molecular Structure 1229 (2021) 129805
Fig. 2. NOE spectrum of compound 5b.
ꢀ
blet at δH 7.82-8.02 ppm assigned to 4 -H, a singlet at 6.66 ppm
assigned to the =CH and a broad singlet at δH 12.13 ppm as-
signed to NH. This agrees with the 1H-NMR (300 MHz, DMSO-
d6) spectrum of 5-(Z)-5-(1,3-benzodioxol-5-ylmethylene)-1-methyl-
2-thioxoimidazolin-4-one [61], whose N1-CH3 appears at δH 3.18
ppm, =CH appears at 6.54 ppm and NH appears at δH 12.22 ppm,
respectively. 1H–NMR (500 MHz, DMSO-d6) spectrum of compound
5b showed a singlet at δH 2.33 ppm assigned to the methyl pro-
ton, a singlet at 3.47 ppm assigned to the methyl proton of N1-
sodium hydride. On the other hand, Compounds 6a-d were pre-
pared from the reaction of 1 with ethyl isothiocyanate in refluxing
ethanol, followed by condensation with aryl carboxaldehyde
derivatives 4a-d in the presence of morpholine. Compounds 7a-d
were prepared from the reaction of 5a-d with ethyl bromoacetate
in anhydrous acetonitrile and sodium hydride. The structural as-
signment of these compounds was fully supported by the physical
data.
The synthetic pathway for the described compounds is il-
lustrated in Scheme 3. The key intermediates for the synthe-
sis of cyclic N-glycosides are shown in Scheme 3. Analogously,
treatment of 5a-d with 1.1 equivalents of NaH in anhydrous
acetonitrile furnished the sodium salts of 2-thioxothiazolidin-4-
ones 8a-d, which in turn were treated with 2,3,4,6-tetra-O-acetyl-
α-D-glucopyranosyl bromide (9a) or 2,3,4,6-tetra-O-acetyl-α-D-
galactopyranosyl bromide (9b) to afford the N-glycosylated nu-
cleosides 10a–h in between medium and good yields (40–90%),
(Scheme 3). Thin layer chromatography (CH2Cl2/MeOH, 98:2) in-
dicated the formation of pure compounds. The structures of the
N-glycoside 10a–h was confirmed by elemental analysis and spec-
tral data (IR, 1H–NMR, 13C–NMR). The 1H–NMR (500 MHz, CDCl3)
spectrum of compound 10a as an example, showed the anomeric
proton of the glucose moiety as a doublet at δ 6.17 ppm with a
ꢀ
CH3, a doublet at δH 7.22 ppm (J = 7.50 Hz) assigned to 2 -H,
ꢀ
ꢀ
6 -H, a doublet at δH 8.02 ppm (J = 8.00 Hz) assigned to 3 -H,
ꢀ
5 -H, a singlet at 6.65 ppm assigned to the =CH and a singlet
at δH 12.50 ppm assigned to NH. This agrees with the 1H-NMR
(300 MHz, DMSO-d6) spectrum of (E)-5-(benzylidene)-1-methyl-2-
thioxoimidazolin-4-one (5a E-form), whose =CH appears at 6.66
ppm and NH appears at δH 12.40 ppm, respectively. The 13C-NMR
(75 MHz, DMSO-d6) spectrum of compound 5d showed an ab-
sorption at δ 118.62, 163.55, 177.15 ppm assigned to the vinyl,
carbonyl and thiocarbonyl groups, respectively, likewise indicating
the presence of a E-configuration for the exocyclic double bond,
in agreement with the 13C-NMR spectra of 3-substituted (E)-5-
(arylidene)-1-methyl-2-thiohydantoin derivatives whose vinyl, car-
bonyl and thiocarbonyl groups appear at δ 115-125, 160-162 and
175-177 ppm, respectively [54]. Furthermore, structures of novel
compounds were confirmed by spectroscopic methods and by el-
emental analyses for C, H, and N. The (E)-configuration around
the exocyclic C=C double bond in compound 5d was determined
by NMR (HMBC technique) based on the magnitude of long-range
2
coupling constant J1’,2’ = 10.50 Hz indicating β-configuration of
the anomeric center. The other protons of the glucopyranose ring
resonated at δ 4.21–6.11 ppm, while the four acetoxy groups ap-
peared as four singlets at δ 1.98–2.09 ppm. The 13C–NMR (125
MHz, CDCl3) revealed the presence of the thione carbon atom at
about 174.58 ppm (Fig. 3). The signals at δ, 169.69, 170.16, 170.72
ppm were due to the four acetoxy carbonyl atoms (4C=O), and
the six signals at δ 61.84, 67.90, 68.13, 73.44, 74.54, 81.98 ppm
were assigned to C-6’,C-2’, C-3’, C-4’, C-5’, and C-1’, respectively.
Moreover, the IR spectra of compounds 10a-h revealed the pres-
ence of the stretching signal of a thione group. These data are
also in agreement with the 13C–NMR (125 MHz, DMSO-d6) spec-
trum of (E)-5-(benzylidene)-3-[2-(4-morpholino)ethyl]-1-methyl-2-
thiohydantoin [64] since the vinylic carbon atom appears at δc
120.39 ppm, indicating the presence of (E)-configuration around
the exocyclic C=C double bond, the carbonyl at C-4 appears at
δc 161.44 ppm and –N1-CS–N3– carbon atom (C-2) appears at δC
176.72 ppm, indicating the presence of N-glycosylation (Fig. 3). The
structural assignment of these compounds was fully supported by
the physical data.
3
heteronuclear coupling constant, JC–H. The magnitude of the cou-
3
pling constant, JC–H = 10.80 Hz, indicates the trans-relationship
between the methylidene proton at the 6–position and the car-
bonyl carbon atom at the 4-position and is also in agreement with
the literature data [62,63]. The (E)-configuration, around the exo-
cyclic double bond C=C in compounds 5b was additionally con-
firmed by NOESY spectroscopy. A small value of NOE between the
protons at the positions 1 (CH3–N) and CHortho indicates the trans-
relationship between these two protons. On the other hand, NOE
was observed between the following protons: a) H3C–N(1)···H(6)
of Ph (11%) and Hortho of Ph···H3C–N(1) (3%) in the case of com-
pound 5b (Fig. 2). The structural assignment of these compounds
was fully supported by the physical data.
The synthetic pathway for the described compounds
is illustrated in Scheme 2. The synthesis started with the
preparation
imidazolidinones 6a-d and ethyl (E)-2-(5-(arylidene)-1-methyl-
4-oxo-2-thioxoimidazolidin-3-yl)acetates 7a-d from (E/Z)-5-
of
(E)-5-(arylidene)-3-ethyl-1-methyl-2-thioxo-4-
The synthetic pathway for the described N-glycosidic com-
pounds is illustrated in Scheme 3. Removal of the acetyl groups
from the glycopyranose moiety of 10a-h with a solution of conc.
HCl/MeOH at 40-50 °C for 2h furnished (E)-5-(arylidene)-1-methyl-
3-(β-D-glycopyranosyl)-2-thioxoimidazolidin-4-ones (11a-h), indi-
cating the presence of N-glycosylation (Scheme 3). The structures
of 11a-h were confirmed by their spectroscopic and mass spec-
(arylidene)-1-methyl-2-thioxoimidazolidin-4-ones 5a-d and ethyl
iodide in the presence of anhydrous acetonitrile and sodium
hydride. Compounds 6a-d were prepared from the reaction of
5a-d with ethyl iodide the presence of anhydrous acetonitrile and
3

A.I. Khodair, S.B. Bakare, M.K. Awad et al.
Journal of Molecular Structure 1229 (2021) 129805
Scheme 1. Synthesis of the target compounds 3 and 5a-d.
Scheme 2. Synthesis of the target compounds 6a-d and 7a-d.
tral data. The mass spectrum of 10a showed a molecular ion
peak at m/z = 380 (M+·, 5%), while the 1H-NMR (500 MHz,
glycosylation. The nucleoside bases 5a-d can be utilized as start-
ing materials for the synthesis of other carbohydrate derivatives as
deoxy, amino and azido nucleosides. The structural assignment of
these compounds was fully supported by the physical data.
CDCl3) spectrum showed a doublet at δH 5.51 with J1ꢀ,2 = 10.00
ꢀ
ꢀ
Hz, corresponding to the 1 -H and indicating a β-configuration.
Vinylic carbon (=CH) of 10a resonated at δC 121.28 ppm, indi-
cating (E)-configuration. Carbon 2 of 10a resonated at δC 180.00
ppm, establishing the N-glycosylation. Furthermore, the heteronu-
clear spectra (HMQC, DFQ-COSY) of 10a-h no such correlation was
2.2. Computational Method
The molecular structures of the investigated compounds were
optimized using DFT (density functional theory) in combination
with the Beck’s three parameter exchange functional along with
ꢀ
shown between N1-CH3 and 1 -H, which is an indication of the N-
4

A.I. Khodair, S.B. Bakare, M.K. Awad et al.
Journal of Molecular Structure 1229 (2021) 129805
Fig. 3. The chemical shift of the corresponding carbon atom at positions 2 and 6 in 5a (Z), 5a (E), 7a (E), and 10a (E).
Scheme 3. Synthesis of the target compounds 10a-h and 11a-h.
5

A.I. Khodair, S.B. Bakare, M.K. Awad et al.
Journal of Molecular Structure 1229 (2021) 129805
Table 1
The calculated quantum chemical parameters obtained from DFT/B3LYP/6-31+G (d,p) of the investigated compounds.
Compound
EHOMO (eV)
ELUMO (eV)
ꢀE (eV)
DM (D)
IP (eV)
EA (eV)
η (eV)
σ (eV−1
)
μ (eV)
χ (eV)
ω
E a. u.
IC50 MC7
6b
-6.280
-6.536
-6.509
-4.887
-4.853
-6.046
-2.170
-2.114
-2.328
-2.006
-1.979
-2.427
4.111
4.421
4.181
2.884
2.874
3.618
3.764
4.631
0.329
3.198
3.200
5.991
6.280
6.536
6.509
4.887
4.853
6.046
2.170
2.114
2.328
2.006
1.979
2.427
2.056
2.211
2.091
1.442
1.437
1.809
0.486
0.452
0.478
0.693
0.696
0.553
4.225
4.325
4.416
3.447
3.416
4.237
-4.225
-4.325
-4.416
-3.447
-3.416
-4.237
4.341
4.230
4.663
4.120
4.060
4.962
-1126.089
-1546.335
-1774.245
-2229.492
-2268.810
-1658.132
ND
6d
12.4
10.43
6.63
5.76
4.3
7d
10a
10g
11b
the Lee-Yang-Parr non local correlation functional (B3LYP) [65-
67] with 6-31+G (d,p) basis set which is implemented in Gaus-
sian 09 program package [68]. An estimate of molecular proper-
ties related to molecular reactivity was calculated with DFT/B3LYP
combination [69]. The molecular properties include the highest oc-
cupied molecular orbital (HOMO), the lowest unoccupied molecu-
lar orbital (LUMO), global hardness and softness, electronegativity,
electron affinity, ionization potential, etc. [60,70–72].
tential, electronegativity and electrophilicity mean increasing the
reactivity of the molecule (10g) and accordingly increases its bio-
logical activity, which agrees well with the experimental observa-
tions, Table 1.
Experimentally, it was shown that the replacing the acetate
moiety on sugar (compounds 10a and 10g) by a hydroxyl moiety
(compound 11b) increases the reactivity. This was confirmed from
the decreasing the energy of LUMO and increasing the dipole mo-
ment of compound (11b), which means that molecule (11b) acts as
an acceptor (electrophile) from the enzyme with high lipophobic
character which is in a good agreement with experimental obser-
vations. The electrophilicity is the descriptor of reactivity and is
sufficient to describe the toxicity of the molecules. It also provides
the direct relationship between the rates of reactions and the abil-
ity to identify the function or capacity of an electrophile and the
electrophilic power of the compounds. It was shown from the cal-
culations that the compound (11b) has higher electrophilicity in-
dex (4.962 eV), than those of compounds (10a and 10g), which
probably enhance its biological activities and agrees well with the
experimental observations, Table 1.
2.3. Quantum Chemical Study
The quantum chemical methods and molecular modelling tech-
niques can define a large number of molecular quantities char-
acterizing the reactivity, shape, and binding properties of a com-
plete molecule as well as of molecular fragments and substituents.
Quantum chemical calculations were performed to investigate the
effect of structural parameters on the biological activity of some
investigated compounds. The optimized molecular structures with
minimum energies obtained from the calculations of the investi-
gated compounds are shown in Fig. 4.
Comparing the reactivity of compound (7d), with substitution
at N-atom, and compound (6d), where the substitution at S-atom,
it was shown experimentally that the biological activity increases
with the substitution on N-atom more than that at S-atom. This
was confirmed theoretically, by increasing the energy of HOMO
level by 0.025 eV which means increasing the donation ability to
the active sites of enzyme, Table 1. On the other side, the abil-
ity of compound (7d) to accept charge from the surrounding is
higher than that of compound (6d), which means that this com-
pound could react as electrophiles. The electrophilicity is the de-
scriptor of reactivity and is sufficient to describe the toxicity of
the molecules. It also provides the direct relationship between the
rates of reactions and the ability to identify the function or ca-
pacity of an electrophile and the electrophilic power of the com-
pounds. It was shown from the calculations that the compound
(7d) has higher electrophilicity (4.663) than that of compound
(6d), (4.230) which probably enhances its biological activity and
agree well with the experimental observations. Also, the calcula-
tions showed that the substituent at N-atom increases the softness,
chemical potential and electronegativity which means increasing
the reactivity of compound (7d), with substituent at S-atom, and
accordingly increases its biological activity, Table 1. This is in a
good agreement with the experimental data.
We started our calculations to make a comparison between the
stability of the investigated compounds in Z- and E-forms and the
calculations showed that they are more stable in the E-form than
Z-form, by about 0.081 au, which is in a good agreement with the
experimental observations. So, we performed DFT calculations on
the stable structures of E-form for all molecules.
The experimental data showed that the presence of sugar moi-
ety at N-atom of five membered ring increases the biological ac-
tivity as in the case of (compounds 10a, 10g and 11b) with re-
spect to the other compounds without sugar moiety (compounds
7d, 6d and 6b), which was confirmed by the calculation. The cal-
culations showed that the insertion of sugar moiety increases the
energy of HOMO to be (-4.887, -4.853 and -6.046 eV) for com-
pounds (10a, 10g and 11b), respectively, which is the donor part
of the molecule, and increases the softness to be (0.693, 0.696 and
0.553 eV−1), respectively, with respect to lower softness for com-
pounds (6b, 6d and 7d) (0.486, 0.452 and 0.478 eV−1), respectively.
It was shown from the calculations that decreasing the energy gap
between HOMO-LUMO for compounds (10a, 10g and 11b) (2.884,
2.874and 3.618 eV), respectively, more than in the case of com-
pounds (6b, 6d and 7d) (4.111, 4.421 and 4.181 eV), restively, which
is probably more favourable for the reactivity of compounds 2, 5
and 7 towards the enzyme. The decreasing of the chemical po-
tential, electronegativity and electrophilicity mean increasing the
reactivity of the molecules (11b, 10a and 10g) and accordingly in-
crease the biological activity, which agrees well with the experi-
mental observations, Table 1.
2.4. Frontier Molecular Orbitals (FMO)
The HOMO and LUMO levels are very common quantum chem-
ical parameters which play a role in determining the way the
molecule interacts with another molecule. The HOMO and the
LUMO levels charge density distribution for the studied molecules
are shown in Fig. 4. It was shown from the investigated com-
pounds that the HOMO levels, which could be reacted as a nu-
cleophile (hydrogen bond acceptor) with the biological target, is
mainly localized on the lone-pair of S, N and keto-oxygen atoms
except phenyl, ethyl acetate and ethyl moieties in the case of com-
Comparing the reactivity between compounds (10a) and (10g),
we noticed that the replacing of H-atom on phenyl moiety (com-
pound 10a) by CH3O-group (compound 10g) increases its reactiv-
ity. This was confirmed from the increasing the energy of HOMO of
molecule (10g) by 0.034 eV, and decreasing its energy gap by 0.01
eV. Also, the increasing the values of dipole moment and softness
of compound (10g) by 0.002 D and 0.003 eV−1, respectively, in-
creases its reactivity. Moreover, the decreasing of the chemical po-
6

A.I. Khodair, S.B. Bakare, M.K. Awad et al.
Journal of Molecular Structure 1229 (2021) 129805
the sugar moiety will not contribute in the LUMO level. The cal-
culations showed that charge transfer may occur from the nucle-
ophilic sites to the electrophilic part of the same molecules. It was
concluded from FMOs that the effect of substituents on the dia-
zole moiety plays an important role to enhance the affinity of the
tested compounds towards the target enzymes.
2.5. Molecular Docking Studies
Table 2 Summarizes the ligand-receptor interactions inside the
2a4l binding site to compare the overall interactions of the docked
compounds with that made by the co-crystallized ligand. From
this comparison, we concluded that compounds might have hu-
man cyclin-dependent kinase activity as the co-crystallized ligand
where they form the same interactions with Leu 83 and Lys 89
which are the key amino acid interactions. So, these promising
derivatives were worthy of being further tested against cancer cell
lines to collect an overview of their biological activity.
2.6. In Vitro Cytotoxic Results
In vitro cytotoxic activity of the tested derivatives was tested
against liver (HepG2) cell line by measuring the percentage of cell
survival against their serial dilutions (1, 10, 100, and 1000 μM).
In vitro cytotoxic activity illustrated the percentage of cell survival
relative to control decreases with increasing concentrations prov-
ing their cytotoxic activities. It decreased in a dose-response curve
that means with increasing concentrations percentage of cell sur-
vival decreased. Moreover, some of the analyzed compounds ex-
hibited a substantial decrease in the percentage of cell survival
than the standard drug itself. As seen in Table 3, 11b was cytotoxic
nearly as the 5-FU by having non-significant IC50 values of 4.3 μM
and 4.34 μM, respectively against MCF-7 cells. Additionally, it had
slightly weaker cytotoxic against HepG2, and A549 with IC50 values
of 5.53 and 9.43 μM, respectively than the 5-FU with IC50 values of
4.43 and 5.54 μM against the corresponding cells.
3. Conclusions
In the present study, we have carried out the successful
synthesis of hitherto unreported (Z/E)-5-(arylidene)-1-methyl-
2-thioxo-4-imidazolidinones
methyl-2-thioxoimidazolidin-4-ones 6a-d, ethyl (E)-5-(arylidene)-
1-methyl-4-oxo-2-thioxoimidazolidin-3-yl)acetate 7a-d, (E)-5-
5a-d,
(E)-5-(arylidene)-3-ethyl-1-
(arylidene)-3-(2’.3’.4’.6’-tetra-O-acetyl-β-D-glycopyranosyl)-1-
methyl-2-thioxoimidazoliden-4-ones 10a-h and (E)-5-(arylidene)-
3-(β-D-glycopyranosyl)-1-methyl-2-thioxoimidazoliden-4-ones
11a-h. The conformational analyses of their most stable configu-
rations were established by NMR spectroscopy. The antiviral and
the further antitumor activities of the new prepared compounds
are under investigation and will be reported in the due time. The
nucleobase 5 can be utilized as starting materials for the synthesis
of other carbohydrate derivatives as deoxy, amino and azido nucle-
osides. The electronic and geometric structures were deduced from
DFT calculations with B3LYP/6-31+G (d) level to analyze the stable
structure of the compounds. The quantum chemical parameters
obtained from the calculations showed a good correlation with the
experimental observations. The synthesized derivatives exhibited
good binding interactions towards the cyclin-dependent kinase 2,
especially compound 11b, which have better key interactions than
the co-crystallized ligand. Additionally, it had potent cytotoxic
activities with IC50 = 4.30, 5.53, 9.43 μM against MCF-7, HepG2,
and A549, respectively. Finally, we recommend further in vivo
cancer model for this compound so that it can be developed as
chemotherapeutic anti-cancer agent.
Fig. 4. The optimized molecular structures, charge density distributions (HOMO
and LUMO) for the investigated compounds.
pounds 6b, 6d and 7d, respectively. But in the case of compounds
10a, 10g and 11b, the sugar and phenyl moieties will not con-
tribute to the HOMO level. The LUMO, which could be reacted as
a nucleophile (hydrogen bond donor) with the biological target,
is mainly delocalized over the whole molecule with π∗ character
except for phenyl, ethyl acetate and ethyl moieties in the case of
compounds 6b, 6d and 7d, but for compounds 10a, 10g and 11b,
7

A.I. Khodair, S.B. Bakare, M.K. Awad et al.
Journal of Molecular Structure 1229 (2021) 129805
Fig. 5. A. Superimposed pose of the docked tested compounds 11b (green) and the co-crystallized ligand (buff) and B. Binding mode of the docked compound 11b and its
molecular interactions inside the binding site of 2a4l receptor.
4. Experimental Section
4.3. General procedure for the preparation of
(Z/E)-5-(arylidene)-1-methyl-2-thioxoimidazolidin-4-ones 5a-d
4.1. General procedures
To
a mixture of 3 (1.30 g, 10 mmol), morpholine (0.09
All melting points were taken on Electrothermal IA 9100 se-
ries digital melting point apparatus. Microanalytical data (in ac-
cord with the calculated values) were performed by Vario, Ele-
mentary apparatus (Shimadzu). The IR spectra (KBr) were recorded
on a Perkin Elmer 1650 spectrometer (USA). 1H–NMR and 13C–
NMR spectra were determined on a JEOL ECA-500. Chemical shifts
were expressed in ppm relative to SiMe4 as internal standards
and DMSO-d6 or CDCl3 or CD3OD as solvent. Mass spectra were
recorded on 70 eV EI Ms-QP 1000 EX (Shimadzu).
g, 10 mmol) and ethanol (30 ml) was added the appropri-
ate aryl carboxaldehydes namely benzaldehyde (4a) (1.27 g,
11 mmol), 4-methylbenzaldehyde (4b) (1.32 g, 11 mmol), 4-
methoxybenzaldehyde (4c) (1.50 g, 11 mmol), and finally 4-
chlorobenzaldehyde (4d) (1.56 g, 11 mmol). The mixture was
stirred at 40-50 °C for 12 h until the starting material was con-
sumed (TLC), cooled to room temperature, deposited with distilled
water (30 ml) and the neutralized with 1 N HCl with stirring for 5
min. The yellow solid separated was filtered off and recrystallized
from ethanol to give the products 5a-d..
4.2. General procedure for the preparation of
1-methyl-2-thioxoimidazoliden-4-one (3)
(Z/E)-5-(Benzylidene)-1-methyl-2-thioxoimidazolidin-4-one
(5a): Yield: 1.20 g (55%) (E/Z ratio, 1.3:1.0). Mp: 202-204 °C. IR
(KBr): v = 3094 (NH), 1714 (C=O), 1364 (CS) cm−1
.
1H-NMR (500
A mixture of N-methyl glycine (1) (0.89 g, 10 mmol) and am-
monium thiocyanate (1.52 g, 20 mmol) was stirred for 4 h at 140-
150 °C in an oil bath until the starting material was consumed
(TLC). The solid residue was washed with methanol and collected
by filtration and recrystallized from ethanol to give 1.45 g (55%)
of 3 as a white solid. Mp 198-200 °C (lit. [63], 90%, 230-232 °C;
lit. [73], 44%, 221-224 °C). IR (KBr): ν 3387 (NH), 1647 (CO), 1319
MHz, DMSO-d6): δ = 3.20 (3H, s, N1-CH3, Z-form), 3.47 (3H, s,
N1-CH3, E-form), 6.63 (1H, s, =CH, E-form), 6.66 (1H, s, =CH, Z-
form), 7.36-8.02 (10H, m, H-Ar, E-form, Z-form), 12.13 ppm (2H, br.
s, NH, E-form, Z-form). 13C-NMR (125 MHz, DMSO-d6): δ = 30.18
(N1-CH3, E-form), 34.11 (N1-CH3, Z-form), 111.57 (=CH, Z-form),
119.38 (=CH, E-form), 128.56, 128.64, 129.58,130.15, 131.08, 131.80,
133.24 (C-5, C-Ar, Z-form, E-form), 162.68 (C-4, E-form), 164.43
(C-4, Z-form), 176.41 (C-2, E-form), 180.04 (C-2, Z-form). MS:
C11 H10N2OS: m/z: 218 (M+·, 64.80%).
(CS) cm−1
.
1H-NMR (500 MHz, DMSO-d6): δ = 3.10 (3H, s, N1-CH3),
4.20 (2H, s, CH2), 11.60 (1H, s, NH). 13C-NMR (125 MHz, DMSO-d6):
δ = 33.32 (N-CH3), 55.70 (CH2), 172.68 (CO), 182.16 (CS).
8

A.I. Khodair, S.B. Bakare, M.K. Awad et al.
Journal of Molecular Structure 1229 (2021) 129805
Table 2
Ligand-receptor interactions for the tested derivatives as inhibitors for Human cyclin-dependent kinase 2.
Binding affinity
(Kcal/mol)
Hydrogen bonds
Van der Waals
Ligands
With amino acid
residues
Bond length
interactions
No.
(A°)
Co-crystallized
ligand
-18.73
2
Leu 83
1.98, 1.23
1 arene-cation
interaction
(PDB2a4l)
with Lys 89
Docked derivatives
6b -10.55
-
-
-
1 arene-cation
interaction
with Lys 89
6d
-7.95
NO binding interactions
-
(continued on next page)
9

A.I. Khodair, S.B. Bakare, M.K. Awad et al.
Journal of Molecular Structure 1229 (2021) 129805
Table 2 (continued)
Ligands
Binding affinity
Hydrogen bonds
Van der Waals
(Kcal/mol)
No.
With amino acid
residues
Bond length
interactions
(A°)
7d
-13.63
1
Lys 89
1.68
-
10a
10g
-18.44
-19.56
2HB Lys 89
Leu 83
fx
1.87
2.01
-
-
2
Lys 89
1.98, 1,76
11b
-21.34
2
2
Leu 83
Lys 89
1.60, 1.77
1.65, 1.60
-
(continued on next page)
10

A.I. Khodair, S.B. Bakare, M.K. Awad et al.
Journal of Molecular Structure 1229 (2021) 129805
Table 2 (continued)
Ligands
Binding affinity
(Kcal/mol)
Hydrogen bonds
Van der Waals
No.
With amino acid
residues
Bond length
interactions
(A°)
Fig. 6. Sigmoidal dose-response curve for the IC50 of 11b against A549, HepG2, and MCF-7 cancer cell lines.
11

A.I. Khodair, S.B. Bakare, M.K. Awad et al.
Journal of Molecular Structure 1229 (2021) 129805
(E)-5-(4-Methylbenzylidene)-1-methyl-2-thioxoimidazolidin-
4-one (5b): Yield: 1.90 g (82%). Mp: 210-212 °C. IR (KBr): v = 3125
(E)-5-(Methylbenzylidene)-3-ethyl-1-methyl-2-
thioxoimidazolidin-4-one (6b): Yield: 0.17 g (61%). Mp: 114-116
(NH), 1734 (CO), 1373 (CS) cm−1
.
1H-NMR (500 MHz, DMSO-d6):
°C. IR (KBr): v = 1720 (CO), 1374 (CS) cm−1
;
1H-NMR (500 MHz,
δ = 2.33 (3H, s, CH3C6H4), 3.47 (3H, s, N1-CH3), 6.65 (1H, s, =CH),
7.22 (2H, d, J = 7.5, Hz, H-3‘, H-5‘), 8.02 (2H, d, J = 8.0 Hz, H-2‘,
H-6‘), 12.50 ppm (1H, s, NH). 13C-NMR (125 MHz, DMSO-d6):
δ = 21.22 (CH3C6H4), 30.17 (N1-CH3), 120.15 (=CH), 129.25, 130.32,
130.41, 131.23, 139.71 (C-Ar and C-5), 164.27 (C-4), 177.56 (C-2).
MS: C12H12N2OS: m/z: 232 (M+·, 78.50%).
CDCl3): δ = 1.20 (3H, t, J =7.0 Hz, CH2CH3), 2.55 (3H, s, CH3C6H4),
3.54 (3H, s, N1-CH3), 3.93 (2H, q, J =7.0 Hz, CH2CH3), 6.39 (1H, s,
=CH), 7.15 (2H, d, J = 8.0 Hz, H-3‘, H-5‘), 7.86 (2H, d, J = 8.0 Hz,
H-2‘, H-6‘). 13C-NMR (125 MHz, CDCl3): δ = 13.06 (CH3CH2), 21.62
(CH3C6H4), 30.47 (N1-CH3), 36.99 (CH3CH2), 120.94 (=CH), 128.40,
129.22, 130.87, 140.61 (C-Ar and C-5), 161.42 (C-4), 176.36 (C-2).
MS: C14 H16 N2OS: m/z: 260 (M+·, 100%). Calculated for C14 H16 N2OS
(260.36): C, 64.58; H, 6.19; N, 10.76. Found: C, 65.03; H, 5.80; N,
10.96.
(E)-5-(4-Methoxylbenzylidene)-1-methyl-2-
thioxoimidazolidin-4-one (5c): Yield: 1.40 g (57%). Mp: 182-184
°C. IR (KBr): v = 3230 (NH), 1718 (CO), 1386 (CS) cm−1
.
1H-NMR
(500 MHz, DMSO-d6): δ = 3.46 (3H, s, N1-CH3), 3.79 (3H, s,
OCH3), 6.66 (1H, s, =CH), 6.96 (2H, d, J = 8.0 Hz, H-2‘, H-6‘) 8.13
(2H, d, J = 7.5 Hz, H3‘,5‘), 12.45 ppm (1H, s, NH). 13C-NMR (125
MHz, DMSO-d6): δ = 30.18 (N1-CH3), 55.76 (OCH3), 114.21, 121.07,
125.68, 128.87, 133.3, 160.91 (=CH, C-5 and C-Ar), 163.06 (C-4),
176.07 (C-2).
(E)-5-(Methoxylbenzylidene)-3-ethyl-1-methyl-2-
thioxoimidazolidin-4-one (6c): Yield: 0.14 g (50%). Mp: 96-100
°C. IR (KBr): v = 1710 (CO), 1384 (CS) cm−1
.
1H-NMR (500 MHz,
CDCl3): δ = 1.29 (3H, t, J =7.0 Hz, CH2CH3), 3.62 (3H, s, N1-CH3),
3.87 (3H, s, OCH3), 4.04 (2H, q, J = 7.0 Hz, CH2CH3), 6.48 (1H, s,
=CH), 6.95 (2H, d, J = 9.0 Hz, H-2‘, H-6‘), 8.09 (2H, d, J = 9.0,
H-2‘, H-6‘). 13C-NMR (125 MHz, CDCl3): δ = 13.09 (CH3CH2), 30.48
(N1-CH3), 36.98 (CH3CH2), 55.42 (OCH3), 121.14 (=CH), 113.95,
124.89, 127.63, 132.71, 133.17, 161.17 (C-Ar and C-5), 161.51 (C-4),
175.86 (C-2). MS: C14 H16 N2O2S: m/z: 276 (M+·, 79%). Calculated for
C14 H16 N2OS (276.36): C, 60.85; H, 5.84; N, 10.14. Found: C, 61.27;
H, 5.76; N, 10.22.
(E)-5-(4-Chlorobenzylidene)-1-methyl-2-thioxoimidazolidin-
4-one (5d): Yield: 1.33 g (53%). Mp: 204-206 °C. IR (KBr): v = 3116
(NH), 1733 (CO), 1314 (CS) cm−1 1H-NMR (500 MHz, DMSO-d6):
.
δ = 3.46 (3H, s, N1-CH3), 6.71 (1H, s, =CH), 7.46 (2H, d, J = 8.0
Hz, H-2‘, H-6‘), 8.07 (2H, d, J = 8.5, H-3‘, H-5‘), 12.50 (1H, br. s,
NH). 13C-NMR (125 MHz, DMSO-d6): δ = 30.20 (N1-CH3), 118.62
(=CH), 128.64, 131.03, 131.98, 132.81,134.24 (C-Ar and C-5), 163.55
(C-4), 177.15 (C-2). MS: C11 H9ClN2OS: m/z: 252(M+·, 69.23%).
(E)-5-(Chlorobenzylidene)-3-ethyl-1-methyl-2-
thioxoimidazolidin-4-one (6d): Yield: 0.15
120 °C. IR (KBr): v = 1718 (CO), 1384 (CS) cm−1
g
(54%). Mp: 118-
1H-NMR (500
.
MHz, CDCl3): δ = 1.29 (3H, t, J =7.0 Hz, CH2CH3), 3.63 (3H, s,
N1-CH3), 4.03 (2H, q, J = 7.0 Hz, CH2CH3), 6.42 (1H, s, =CH),
7.39 (2H, d, J = 9.0 Hz, H-2‘, H-6‘), 8.09 (2H, d, J = 9.0 Hz, H-2‘,
H-6‘). 13C-NMR (125 MHz, CDCl3): δ = 13.04 (CH3CH2), 30.45
(N1-CH3), 37.07 (CH3CH2), 118.73 (=CH), 128.76, 129.60, 130.56,
132.02, 135.76 (C-Ar and C-5), 161.40 (C-4), 176.74 (C-2). MS:
C13H13ClN2OS: m/z: 280 (M+·, 92%). Calculated for C13H13ClN2OS
(280.77): C, 55.61; H, 4.67; N, 9.98. Found: C, 55.78; H, 4.58; N,
9.96.
4.4. General procedure for the preparation of
(E)-5-(arylidene)-3-ethyl-1-methyl-2-thioxoimidazolidin-4-ones 6a-d
Method A: A mixture of 5-((E)-arylidene)-1-methyl-2-thioxo-4-
imidazolidinones 5a-d (1 mmol), anhydrous acetonitrile (10 mL)
and sodium hydride (45 mg, 80%) was stirred at room tempera-
ture for ½ hour. Ethyl bromide (0.22 g, 2 mmol) was added to the
mixture with stirring at 40-50 °C until the starting material was
consumed (4 h; TLC, ethyl acetate/chloroform, 95:5) and cooled at
room temperature. Then solvent was removed under reduced pres-
sure and the residue was treated with cold water. The solid sepa-
rated was collected by filtration and recrystallized from ethanol to
give the products 6a-d in quantitative yields.
Method B: A mixture of N-methyl glycine (1) (0.89 g, 10 mmol)
and ethyl isothiocyanate (0.96 g, 11 mmol) and anhydrous ethanol
(30 ml) was stirred with refluxing for 4 h until the starting ma-
terial was consumed (TLC). Then morpholine (0.09 g, 10 mmol)
and the appropriate aryl carboxaldehydes namely benzaldehyde
(4a) (1.27 g, 11 mmol), 4-methylbenzaldehyde (4b) (1.32 g, 11
mmol), 4-methoxybenzaldehyde (4c) (1.50 g, 11 mmol), and finally
4-chlorobenzaldehyde (4d) (1.56 g, 11 mmol) were added to the
reaction mixture. The mixture was stirred at 40-50 °C for 12 h
until the starting material was consumed (TLC), cooled to room
temperature, deposited with distilled water (30 ml) and the neu-
tralized with 1 N HCl with stirring for 5 min. The yellow solid
separated was filtered off and recrystallized from ethanol to give
the products 6a (30%), 6b (35%), 6c (16%), 6d (35%), respectively.
They were identical with authentic samples, which were prepared
(E)-5-(Benzylidene)-3-ethyl-1-methyl-2-thioxoimidazolidin-4-
one (6a): Yield: 0.23 g (89%). Mp: 140-142 °C. IR (KBr): v = 1720
(CO), 1396 (CS) cm−1
;
1H-NMR (500 MHz, CDCl3): δ = 1.28 (3H,
t, J = 7.0 Hz, CH2CH3), 3.59 (3H, s, N1-CH3), 4.26 (2H, q, J = 7.0
Hz, CH2CH3), 6.46 (1H, s, =CH), 7.41 (3H, m, H-Ar), 8.01 (2H, d,
J = 6.5 Hz, H-Ar). 13C-NMR (125 MHz, CDCl3): δ = 13.09 (CH3CH2),
30.45 (N1-CH3), 37.01 (CH3CH2), 120.45 (=CH), 128.40, 129.51,
129.92, 130.76, 132.04 (C-Ar and C-5), 161.35 (C-4), 176.60 (C-2).
MS: C13H14 N2OS: m/z: 246 (M+·, 100%). Calculated for C13H14 N2OS
(246.33): C, 63.39; H, 5.73; N, 11.37. Found: C, 63.41; H, 5.14; N,
11.10.
Table 3
IC50 for the in vitro cytotoxic activity of the tested compounds against MCF-7, HepG2,
A549, and HCT116 cell lines.
Compounds
IC50 (μM)∗
Breast MCF-7
Liver HepG2
Lung A549
Colon HCT116
6b
ND
17.8
˃50
ND
26.7
ND
ND
6d
12.4
10.43
6.63
5.76
4.30
4.23
16.7
˃50
7.98
8.76
˃50
ND
7d
12.4
18.54
ND
10a
10g
11b
5-FU
ND
˃50
5.53
4.43
9.43
5.54
∗
values are expressed as Mean of three independent replicates.
12

A.I. Khodair, S.B. Bakare, M.K. Awad et al.
Journal of Molecular Structure 1229 (2021) 129805
in method A, by melting points, mixed melting points and TLC
determinations.
4.6. General procedure for the preparation of
(E)-5-(arylidene)-3-(2’.3’.4’.6’-tetra-O-acetyl-β-D-glucopyranosyl)-1-
methyl-2-thioxoimidazoliden-4-ones
10a-h
4.5. General procedure for the preparation of ethyl
(E)-5-(arylidene)-1-methyl-4-oxo-2-thioxoimidazolidin-3-yl)acetates
The nucleobases 5a-d (5mmol) were suspended in anhy-
drous acetonitrile (25 mL) at room temperature. To this sus-
pension was added NaH (80% in mineral oil, 0.15 g, 5 mmol),
and the mixture was stirred at room temperature for ½ hour.
2 ,3 ,4 ,6 -Tetra-O-acetyl-α-D-glycopyranosyl bromides (8a,b, 2.66
g, 5.50mmol) was added, and the mixture was stirred at room
temperature for 12 hours until the starting material was con-
sumed (TLC, CH2Cl2/MeOH, 98:2). The solvent was removed un-
der reduced pressure and then treated with water. The solid
separated was collected by filtration and recrystallized from
ethanol to give the products 10a-h in moderate and quantitative
yields.
7a-d
A mixture of (E)-5-(arylidene)-1-methyl-2-thioxoimidazolidin-
4-ones 5a-d (1 mmol), anhydrous acetonitrile (10 mL) and sodium
hydride (45 mg, 80%) was stirred at room temperature for ½ hour.
ethyl bromoacetate (0.33 g, 2 mmol) was added to the mixture
with stirring at 40-50 °C until the starting material was consumed
(4 h; TLC, ethyl acetate/chloroform, 95:5) and cooled at room tem-
perature. Then solvent was removed under reduced pressure and
the residue was treated with cold water. The solid separated was
collected by filtration and recrystallized from ethanol to give the
products 7a-d in quantitative yields.
ꢀ
ꢀ ꢀ ꢀ
(E)-5-(Benzylidene)-3-(2’.3’.4’.6’-tetra-O-acetyl-β-D-
Ethyl
(E)-5-(benzylidene)-1-methyl-4-oxo-2-
glucopyranosyl)-1-methyl-2-thioxoimidazoliden-4-one
(10a):
thioxoimidazolidin-3-yl)acetate (7a): Yield: 0.30 g (87%). Mp:
186-188 °C. IR (KBr): v = 1733, 1689 (2CO), 1392 (CS) cm−1
.
Yield: 0.80 g (64%). Mp: 186-188 °C. IR (KBr): v = 1755 (CO), 1393
(CS) cm−1
.
1H-NMR (500 MHz, CDCl3): δ = 1.98 (3H, s, Ac), 2.04
1H-NMR (500 MHz, CDCl3): δ = 1.33 (3H, t, J = 7.0 Hz, CH2CH3),
3.37 (3H, s, N1-CH3), 4.21 (2H, s, SCH2), 4.28 (2H, q, J = 7.0 Hz,
CH2CH3), 6.46 (1H, s, =CH), 7.34 (3H, m, H-Ar), 8.18 (2H, d, J = 6.5
Hz, H-Ar). 13C-NMR (125 MHz, CDCl3): δ = 14.11 (CH3CH2), 30.35
(N1-CH3), 34.17 (SCH2), 62.50 (CH3CH2), 121.89 (=CH), 128.45,
129.39, 129.57, 130.11, 131.02 (C-Ar and C-5), 167.67 (C-4), 173.28
(COester), 176.22 (C-2). Calculated for C15H16 N2O3S (304.37): C,
59.19; H, 5.30; N, 9.20. Found: C, 59.09; H, 4.80; N, 9.03.
(3H, s, Ac), 2.07 (3H, s, Ac), 2.09 (3H, s, Ac), 3.64 (3H, s, N3-CH3),
ꢀ
ꢀ
ꢀ
3.88 (1H, m, H-5 ), 4.21 (2H, m, H-6 , H-6 ’), 5.28 (1H, t, J = 9.50
ꢀ
ꢀ
Hz, 4 -H), 5.40 (1H, t, J = 10.0 Hz, 2 -H), 6.11 (1H, t, J = 9.0
Hz, 3 -H), 6.17 (1H, d, 2J 1’,2’= 10.5 Hz, 1 -H), 6.55 (1H, s, =CH),
ꢀ
ꢀ
7.97 (3H, m, H-Ar), 7.29 (2H, d, J = 6.5 Hz, H-Ar). 13C-NMR (125
ꢀ
MHz, CDCl3): δ = 20.62, 20.79 (4Ac), 31.49 (N3-CH3), 61.84 (C-6 ),
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
67.90 (C-2 ), 68.13 (C-3 ), 73.44 (C-4 ), 74.54 (C-5 ), 81.98 (C-1 ),
121.28 (=CH), 128.28, 128.44, 130.21, 131.00, 131.57 (C-Ar and C-5),
159.90 (C-4), 169.38, 169.69, 170.16, 170.72 (4Ac), 174.58 (C-2). MS:
C25H28N2O10S: m/z: 548 (M+·, 5%).
Ethyl
(E)-5-(methylbenzylidene)-1-methyl-4-oxo-2-
thioxoimidazolidin-3-yl)acetate (7b): Yield: 0.32 g (99%); Mp:
164-166 °C. IR (KBr): v = 1734, 1683 (2CO), 1394 (CS) cm−1
;
1H-NMR (500 MHz, CDCl3): δ = 1.32 (3H, t, J = 7.0 Hz, CH2CH3),
2.39 (3H, s, CH3C6H4), 3.36 (3H, s, N1-CH3), 4.21 (2H, s, SCH2),
4.28 (2H, q, J = 7.0 Hz, CH2CH3), 6.44 (1H, s, =CH), 7.23 (2H, d,
J = 8.0 Hz, H-3‘, H-5‘), 8.10 (2H, d, J = 8.0 Hz, H-2‘, H-6‘). 13C-
NMR (125 MHz, CDCl3): δ = 14.11 (CH3CH2), 21.64 (CH3), 30.32
(N1-CH3), 34.49 (SCH2), 62.47 (CH3CH2), 122.20 (=CH), 129.22,
129.55, 131.13, 133.48 (C-Ar and C-5), 167.73 (C-4), 173.40 (COester),
175.56 (C-2). MS: C16 H18 N2O3S: m/z: 318 (M+·, 0.2%). Calculated
for C16 H18 N2O3S (318.39): C, 60.36; H, 5.70; N, 8.80. Found: C,
60.55; H, 5.72; N, 8.83.
(E)-5-(Methylbenzylidene)-3-(2’.3’.4’.6’-tetra-O-acetyl-β-D-
glucopyranosyl)-1-methyl-2-thioxoimidazoliden-4-one
(10b):
Yield: 1.12 g (40%). Mp: 218-220 °C. IR (KBr): v = 1750 (CO),
1388 (CS) cm−1
.
1H-NMR (500 MHz, CDCl3): δ = 1.97 (3H, s, Ac),
2.04 (3H, s, Ac), 2.06 (3H, s, Ac), 2.09 (3H, s, Ac), 2.80 (3H, s,
ꢀ
CH3C6H4), 3.61 (3H, s, N3-CH3), 3.87 (1H, m, H-5 ), 4.92 (2H, m,
ꢀ
ꢀ
ꢀ
H-6 , H-6 ’), 5.26 (1H, t, J = 9.5 Hz, 4 -H), 5.37 (1H, t, J = 10.0
Hz, 2 -H), 6.10 (1H, t, J = 9.0 Hz, 3 -H), 6.12 (1H, d, 2J 1’,2’= 10.5
ꢀ
ꢀ
ꢀ
Hz, 1 -H), 6.46 (1H, s, =CH), 7.38 (2H, d, J = 8.5 Hz, H-3‘, H-5‘),
7.92 (2H, d, J = 8.0 Hz, H-2‘, H-6‘). 13C-NMR (125 MHz, CDCl3):
ꢀ
δ = 20.60, 20.78 (4Ac), 20.78 (CH3), 31.44 (N3CH3), 61.80 (C-6 ),
Ethyl
(E)-5-(methoxylbenzylidene)-1-methyl-4-oxo-2-
(98%). Mp:
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
67.53 (C-2 ), 67.87 (C-3 ), 73.33 (C-4 ), 74.55 (C-5 ), 81.97 (C-1 ),
120.04 (=CH), 128.59, 128.68, 130.11, 132.26, 136.06 (C-Ar and
C-5), 159.96 (C-4), 169.37, 169.74, 170.11, 170.67 (4Ac), 175.96
(C-2). MS: C25H28N2O10S: m/z: 562 (M+·, 9%).
thioxoimidazolidin-3-yl)acetate (7c): Yield: 0.32
g
176-178 °C. IR (KBr): v = 1726, 1680 (2CO), 1390 (CS) cm−1
.
1H-NMR (500 MHz, CDCl3): δ = 1.31 (3H, t, J = 7.0 Hz, CH2CH3),
3.34 (3H, s, N1-CH3), 3.86 (3H, s, OCH3), 4.20 (2H, s, SCH2), 4.27
(2H, q, J = J =7.0 Hz, CH2CH3), 6.41 (1H, s, =CH), 6.93 (2H, d,
J = 8.5, H-2‘, H-6‘), 8.24 (2H, d, J = 8.5, H-3‘, H-5‘). 13C-NMR (125
MHz, CDCl3): δ = 14.12 (CH3CH2), 30.32 (N1-CH3), 34.10 (SCH2),
55.38 (OCH3), 62.46 (CH3CH2), 114.04, 125.24, 131.39, 132.50,
133.24, 160.18 (=CH, C-Ar and C-5), 167.78 (C-4), 173.56 (COester),
174.67 (C-2). MS: C16 H18 N2O4S: m/z: 334 (M+·, 5%). Calculated for
C16 H18 N2O4S (334.39): C, 57.47; H, 5.43; N, 8.38. Found: C, 57.45;
H, 5.27; N, 8.32.
(E)-5-(Methoxylbenzylidene)-3-(2’.3’.4’.6’-tetra-O-acetyl-β-
D-glucopyranosyl)-1-methyl-2-thioxoimidazoliden-4-one (10c):
Yield: 2.40 g (83%). Mp: 224-226 °C. IR (KBr): v = 1742 (CO),
1384 (CS) cm−1
.
1H-NMR (500 MHz, CDCl3): δ = 1.99 (3H, s,
Ac), 2.05 (3H, s, Ac), 2.07 (3H, s, Ac), 2.09 (3H, s, Ac), 3.64 (3H,
ꢀ
s, N3-CH3), 3.88 (3H, s, OCH3), 4.22 (1H, m, H-5 ), 4.25 (2H, m,
ꢀ
ꢀ
ꢀ
H-6 , H-6 ’), 5.29 (1H, t, J = 9.5 Hz, 4 -H), 5.37 (1H, t, J = 10.0
Hz, 2 -H), 6.14 (1H, t, J = 9.0 Hz, 3 -H), 6.16 (1H, d, 2J 1’,2’= 10.5
ꢀ
ꢀ
ꢀ
Hz, 1 -H), 6.52 (1H, s, =CH), 6.96 (2H, d, J = 8.5 Hz, H-2‘, H-6‘),
Ethyl
(E)-5-(chlorobenzylidene)-1-methyl-4-oxo-2-
8.05 (2H, d, J = 8.0 Hz, H-3‘, H-5‘). 13C-NMR (125 MHz, CDCl3):
thioxoimidazolidin-3-yl)acetate (7d): Yield: 0.30 g (92%). Mp:
ꢀ
160-162 °C. IR (KBr): v = 1733, 1684 (2CO), 1395 (CS) cm−1
.
δ = 20.62, 20.79 (4Ac), 31.51 (N3CH3), 55.41 (OCH3), 61.88 (C-6 ),
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
1H-NMR (500 MHz, CDCl3): δ = 1.33 (3H, t, J = 7.0 Hz, CH2CH3),
3.38 (3H, s, N1-CH3), 4.21 (2H, s, SCH2), 4.29 (2H, q, J = J =7.0 Hz,
CH2CH3), 6.39 (1H, s, =CH), 7.39 (2H, d, J = 9.0 Hz, H-2‘, H-6‘),
8.15 (2H, d, J = 8.5 Hz, H-3‘, H-5‘). 13C-NMR (125 MHz, CDCl3):
δ = 14.12 (CH3CH2), 30.37 (N1-CH3), 34.24 (SCH2), 62.50 (CH3CH2),
120.39 (=CH), 128.69, 130.84, 132.31, 134.25, 135.96 (C-Ar and
C-5), 167.59 (C-4), 173.17 (COester), 174.58 (C-2). Calculated for
C16 H18 N2O4S (338.81): C, 53.17; H, 4.46; N, 8.27. Found: C, 53.27;
H, 4.15; N, 8.15.
67.94 (C-2 ), 68.08 (C-3 ), 73.53 (C-4 ), 74.51 (C-5 ), 81.95 (C-1 ),
113.97, 122.35, 124.47, 126.59, 133.32, 158.96 (=CH, C-Ar and C-5),
161.42 (C-4), 169.39, 169.63, 170.14, 170.70 (4Ac), 175.19 (C-2). MS:
C26H30N2O11 S: m/z: 578 (M+·, 3%).
(E)-5-(Chlorobenzylidene)-3-(2’.3’.4’.6’-tetra-O-acetyl-β-D-
glucopyranosyl)-1-methyl-2-thioxoimidazoliden-4-one
(10d):
Yield: 1.40 g (47%). Mp: 233-235 °C. IR (KBr): v = 1751 (CO), 1388
(CS) cm−1
.
1H-NMR (500 MHz, CDCl3): δ = 1.97 (3H, s, Ac), 2.04
(3H, s, Ac), 2.07 (3H, s, Ac), 2.09 (3H, s, Ac), 3.62 (3H, s, N3-CH3),
13

A.I. Khodair, S.B. Bakare, M.K. Awad et al.
Journal of Molecular Structure 1229 (2021) 129805
ꢀ
ꢀ
ꢀ
3.87 (1H, m, H-5 ), 4.26 (2H, m, H-6 , H-6 ’), 5.27 (1H, t, J = 9.5
and C-5), 161.36 (C-4), 165.32, 168.60, 169.12, 170.70 (4Ac), 175.76
(C-2). MS: C25H27ClN2O10S: m/z: 582 (M+·, 1%).
ꢀ
ꢀ
Hz, 4 -H), 5.38 (1H, t, J = 10.0 Hz, 2 -H), 6.09 (1H, t, J = 9.0 Hz,
3 -H), 6.15 (1H, d, 2J 1’,2’= 10.5 Hz, 1 -H), 6.52 (1H, s, =CH), 7.23
(2H, d, J = 8.5 Hz, H-2‘, H-6‘), 7.89 (2H, d, J = 8.0 Hz, H-3‘, H-5‘).
13C-NMR (125 MHz, CDCl3): δ = 20.62, 20.65 (4Ac), 31.49 (N3CH3),
(E)-5-(Arylidene)-3-(β-D-glycopyranosyl)-1-methyl-2-
thioxoimidazoliden-4-ones 11a-h
ꢀ
ꢀ
The protected nucleosides 10a-h (1 mmol) were suspended in
MeOH (15 mL), and concentrated HCl (0.5 mL) was added. The
reaction mixture was stirred at 40-50°C for 2 h, then cooled to
room temperature. To the resulting solution was added an ion-
exchange resin (Amberlite IR-120, HO -form), previously washed
with MeOH. After stirring for 5 min., the solution was filtered and
evaporated in vacuum and the residue was purified by flash chro-
matography (eluent 0–5%, CHCl3/MeOH) to afford 11a-h as yellow
solids.
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
61.86 (C-6 ), 67.92 (C-2 ), 68.11 (C-3 ), 73.49 (C-4 ), 74.52 (C-5 ),
ꢀ
81.96 (C-1 ), 121.24 (=CH), 127.65, 128.87, 129.22, 131.14, 140.94
(C-Ar and C-5), 161.38, 169.38, 169.63, 170.15, 170.71 (4Ac, C-4),
175.67 (C-2). MS: C25H27ClN2O10S: m/z: 582 (M+·, 4%).
(E)-5-(Benzylidene)-3-(2’.3’.4’.6’-tetra-O-acetyl-β-D-
galactopyranosyl)-1-methyl-2-thioxoimidazoliden-4-one (10e):
Yield: 1.90 g (69%). Mp: 76-78 °C. IR (KBr): v = 1751 (CO), 1373
(CS) cm−1
.
1H-NMR (500 MHz, CDCl3): δ = 2.05 (3H, s, Ac), 2.08
(3H, s, Ac), 2.26 (3H, s, Ac), 2.41 (3H, s, Ac), 3.36 (3H, s, N3-CH3),
ꢀ
(E)-5-(Benzylidene)-3-(β-D-glucopyranosyl)-1-methyl-2-
thioxoimidazoliden-4-one (11a): Yield: 0.36 g (95%). Mp: 94-96
ꢀ
ꢀ
4.10 (1H, m, H-5 ), 4.30 (2H, m, H-6 , H-6 ’), 5.25 (1H, t, J = 9.5 Hz,
4 -H), 5.50 (1H, t, J = 10.0 Hz, 2 -H), 6.02 (1H, t, J = 9.5 Hz, 3 -H),
1’,2’
°C. IR (KBr): v = 3500 (OH), 1734 (CO), 1390 (CS) cm−1
.
1H-NMR
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
6.20 (1H, d, 2J
= 9.5 Hz, 1 -H), 7.00 (1H, s, =CH), 7.27 (3H, m,
(500 MHz, DMSO-d6): δ = 3.13 (1H, m, H-5 ), 3.15 (2H, m, H-6 ,
ꢀ
ꢀ
H-Ar), 7.29 (2H, d, J = 6.5 Hz, H-Ar). 13C-NMR (125 MHz, CDCl3):
H-6 ’), 3.21 (1H, t, J = 9.5 Hz, 4 -H), 3.28 (3H, s, N3-CH3), 3.70
ꢀ
ꢀ
ꢀ
ꢀ
δ = 20.71(4Ac), 31.95 (N3-CH3), 63.43 (C-6 ), 65.88 (C-2 ), 66.87
(1H, t, J = 10.0 Hz, 3 -H), 4.32 (1H, t, J = 10.0 Hz, 2 -H), 4.61
ꢀ
ꢀ
ꢀ
ꢀ
(C-3 ), 71.84 (C-4 ), 73.20 (C-5 ), 82.44 (C-1 ), 116.00 (=CH), 128.00,
128.46, 129.58 130.52 131.20, (C-Ar and C-5), 165.00 (C-4), 168.00,
169.00, 170.00, 171.00 (4Ac), 173.00 (C-2). MS: C25H28N2O10S: m/z:
548 (M+·, 2%).
(1H, s, 6’-OH), 5.07 (1H, s, 4’-OH), 5.16 (1H, s, 3’-OH), 5.30 (1H,
2
ꢀ
s, 2’-OH), 5.51 (1H, d, J1’,2’= 10.0 Hz, 1 -H), 6.91 (1H, s, =CH),
7.43 (3H, m, H-Ar), 7.51 (2H, d, J = 6.6 Hz, H-Ar). 13C-NMR (125
ꢀ
ꢀ
MHz, DMSO-d6): δ = 31.55 (N3-CH3), 62.88 (C-6 ), 67.50 (C-2 ),
ꢀ
ꢀ
ꢀ
ꢀ
(E)-5-(Methylbenzylidene)-3-(2’.3’.4’.6’-tetra-O-acetyl-β-D-
galactopyranosyl)-1-methyl-2-thioxoimidazoliden-4-one
70.72 (C-3 ), 79.77 (C-4 ), 80.64 (C-5 ), 85.81 (C-1 ), 115.00, 128.20,
128.50, 129.90, 131.00, 132.30 (=CH, C-Ar and C-5), 163.00 (C-4),
180.00 (C-2). MS: C17 H20N2O6S: m/z: 380 (M+·, 5%).
(10f):
Yield: 2.53 g (90%). Mp: 72-74 °C. IR (KBr): v = 1751 (CO), 1376
(CS) cm−1
.
1H-NMR (500 MHz, CDCl3): δ = 1.91 (3H, s, Ac), 1.93
(E)-5-(Methylbenzylidene)-3-(β-D-glucopyranosyl)-1-methyl-
2-thioxoimidazoliden-4-one (11b): Yield: 0.36 g (92%). Mp:
(3H, s, Ac), 1.95 (3H, s, Ac), 1.97 1.95 (3H, s, Ac), 2.18 (3H, s,
CH3C6H4), 3.25 (3H, s, N3-CH3), 3.90 (1H, m, H-5 ), 4.20 (2H, m,
ꢀ
234-238 °C. IR (KBr): v = 3600 (OH), 1701 (CO), 1397 (CS) cm−1
.
ꢀ
1H-NMR (500 MHz, DMSO-d6): δ = 3.11 (1H, m, H-5 ), 3.12 (2H,
ꢀ
ꢀ
ꢀ
H-6 , H-6 ’), 5.10 (1H, t, J = 10.0 Hz, 4 -H), 5.40 (1H, t, J = 10.0
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Hz, 2 -H), 5.90 (1H, t, J = 9.0 Hz, 3 -H), 6.29 (1H, d, 2J 1’,2’= 10.0
m, H-6 , H-6 ’), 3.20 (1H, t, J = 9.5 Hz, 4 -H), 3.42 (3H, s, N3-CH3),
ꢀ
ꢀ
Hz, 1 -H), 6.90 (1H, s, =CH), 7.20 (2H, d, J = 8.5 Hz, H-3‘, H-5‘),
3.44 (3H, s, CH3C6H4), 3.70 (1H, t, J = 10.0 Hz, 3 -H), 4.61 (1H, t,
ꢀ
7.33 (2H, d, J = 8.0 Hz, H-2‘, H-6‘). 13C-NMR (125 MHz, CDCl3):
J = 10.0 Hz, 2 -H), 4.62 (1H, s, 6’-OH), 5.07 (1H, s, 4’-OH), 5.12 (1H,
ꢀ
2
ꢀ
δ = 20.74 (4Ac), 29.71 (CH3), 31.45 (N3CH3), 61.43 (C-6 ), 65.88
s, 3’-OH), 5.29 (1H, s, 2’-OH), 5.56 (1H, d, J1’,2’= 10.0 Hz, 1 -H),
6.85 (1H, s, =CH), 7.26 (2H, d, J = 8.5 Hz, H-3‘, H-5‘), 7.99 (2H, d,
J = 8.0 Hz, H-2‘, H-6‘). 13C-NMR (125 MHz, DMSO-d6): δ ꢀ= 31.13
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
(C-2 ), 66.86 (C-3 ), 71.82 (C-4 ), 73.22 (C-5 ), 82.45 (C-1 ), 116.14
(=CH). 128.45, 129.50, 131.05, 132.28, 136.04 (C-Ar and C-5),
160.98 (C-4), 168.00, 169.00, 170.00, 171.00 (4Ac), 173.00 (C-2).
MS: C25H28N2O10S: m/z: 562 (M+·, 31%).
ꢀ
ꢀ
(CH3), 31.60 (N3-CH3), 62.84 (C-6 ), 67.52 (C-2 ), 70.68 (C-3 ), 79.76
ꢀ
ꢀ
ꢀ
(C-4 ), 80.66 (C-5 ), 85.86 (C-1 ), 122.00 (=CH), 128.20, 128.90,
129.10, 129.90, 131.10 (C-Ar and C-5), 162.84 (C-4), 178.92 (C-2).
MS: C18 H22N2O6S: m/z: 394 (M+·, 42%).
(E)-5-(Methoxybenzylidene)-3-(2’.3’.4’.6’-tetra-O-acetyl-β-D-
galactopyranosyl)-1-methyl-2-thioxoimidazoliden-4-one (10g):
Yield: 2.50 g (87%). Mp: 58-60 °C. IR (KBr): v = 1750(C O), 1394
(E)-5-(Methoxybenzylidene)-3-(β-D-glucopyranosyl)-1-
methyl-2-thioxoimidazoliden-4-one (11c): Yield: 0.38 g (93%).
(CS) cm−1
.
1H-NMR (500 MHz, CDCl3): δ = 2.03 (3H, s, Ac), 2.05
(3H, s, Ac), 2.08 (3H, s, Ac), 2.26 (3H, s, Ac), 3.39 (3H, s, N3-CH3),
ꢀ
Mp: 222-224 °C. IR (KBr): v = 3422 (OH), 1733 (CO), 1370 (CS)
3.88 (3H, s, OCH3), 4.05 (1H, m, H-5 ), 4.30 (2H, m, H-6 , H-6 ’),
cm−1
.
1H-NMR (500 MHz, DMSO-d6): δ = 3.11 (1H, m, H-5 ), 3.20
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
5.15 (1H, t, J = 10.0 Hz, 4 -H), 5.50 (1H, t, J = 10.0 Hz, 2 -H), 6.10
(2H, m, H-6 , H-6 ’), 3.25 (1H, t, J = 10.0 Hz, 4 -H), 3.34 (3H, s,
ꢀ
ꢀ
ꢀ
(1H, t, J = 9.0 Hz, 3 -H), 6.25 (1H, d, 2J 1’,2’= 10.0 Hz, 1 -H), 6.85
(1H, s, =CH), 7.00 (2H, d, J = 8.5 Hz, H-2‘, H-6‘), 7.30 (2H, d, J = 8.0
Hz, H-3‘, H-5‘). 13C-NMR (125 MHz, CDCl3): δ = 20.74 (4Ac), 29.38
N3-CH3), 3.44 (3H, s, OCH3), 4.32 (1H, t, J = 10.0 Hz, 3 -H), 5.19
ꢀ
(1H, t, J = 10.0 Hz, 2 -H), 4.68 (1H, s, 6’-OH), 5.12 (1H, s, 4’-OH),
2
5.24 (1H, s, 3’-OH), 5.30 (1H, s, 2’-OH), 5.52 (1H, d, J1’,2’= 10.0
ꢀ
ꢀ
ꢀ
ꢀ
(N3CH3), 55.52 (OCH3), 61.88 (C-6 ), 66.00 (C-2 ), 67.00 (C-3 ),
Hz, 1 -H), 6.85 (1H, s, =CH), 7.48 (2H, d, J = 8.5, H-2‘, H-6‘),
72.00 (C-4 ), 74.00 (C-5 ), 82.00 (C-1 ), 114.03, 122.50, 128.00,
129.00, 131.36, 159.67 (=CH, C-Ar and C-5), 161.40 (C-4), 169.38,
169.61, 170.16, 170.75 (4Ac), 175.20 (C-2). MS: C26H30N2O11 S: m/z:
578 (M+·, 2%).
8.14 (2H, d, J = 8.5, H-3‘, H-5‘). 13C-NMR (125 MHz, DMSO-d6):
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
δ = 30.98 (N3CH3), 55.25 (OCH3), 62.68 (C-6 ), 67.72 (C-2 ), 70.68
ꢀ
ꢀ
ꢀ
ꢀ
(C-3 ), 79.74 (C-4 ), 80.60 (C-5 ), 85.78 (C-1 ), 114.35, 115.65, 121.12,
132.74, 133.82, 148.45 (=CH, C-Ar and C-5), 162.52 (C-4), 178.82
(C-2). MS: C18 H22N2O7S: m/z: 410 (M+·, 5%).
(E)-5-(Chlorobenzylidene)-3-(2’.3’.4’.6’-tetra-O-acetyl-β-D-
galactopyranosyl)-1-methyl-2-thioxoimidazoliden-4-one (10h):
Yield: 2.26 g (76%). Mp: 84-86 °C. IR (KBr): v = 1750 (CO), 1394
(E)-5-(Chlorobenzylidene)-3-(β-D-glucopyranosyl)-1-methyl-
2-thioxoimidazoliden-4-one (11d): Yield: 0.36
g (92%). Mp:
(CS) cm−1
.
1H-NMR (500 MHz, CDCl3): δ = 1.91 (3H, s, Ac), 1.95
98-100 °C. IR (KBr): v = 3400 (OH), 1734 (CO), 1389 (CS) cm−1
.
ꢀ
(3H, s, Ac), 1.98 (3H, s, Ac), 2.17 (3H, s, Ac), 3.23 (3H, s, N3-CH3),
ꢀ
1H-NMR (500 MHz, DMSO-d6): δ = 3.12 (1H, m, H-5 ), 3.20 (2H,
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
3.97 (1H, m, H-5 ), 4.20 (2H, m, H-6 , H-6 ’), 5.10 (1H, t, J = 10.0
m, H-6 , H-6 ’), 3.24 (1H, t, J = 10.0 Hz, 4 -H), 3.30 (3H, s, N3-CH3),
ꢀ
ꢀ
ꢀ
ꢀ
Hz, 4 -H), 5.49 (1H, t, J = 10.0 Hz, 2 -H), 5.59 (1H, t, J = 9.00 Hz,
3.70 (1H, t, J = 10.0 Hz, 3 -H), 4.32 (1H, t, J = 10.0 Hz, 2 -H), 4.52
3 -H), 6.10 (1H, d, 2J 1’,2’= 10.0 Hz, 1 -H), 6.54 (1H, s, =CH), 7.19
(2H, d, J = 8.5 Hz, H-2‘, H-6‘), 7.50 (2H, d, J = 8.0 Hz, H-3‘, H-5‘).
13C-NMR (125 MHz, CDCl3): δ = 20.74 (4Ac), 29.72 (N3CH3), 61.42
(1H, s, 6’-OH), 5.05 (1H, s, 4’-OH), 5.15 (1H, s, 3’-OH), 5.30 (1H, s,
ꢀ
ꢀ
2
ꢀ
2’-OH), 5.52 (1H, d, J1’,2’= 10.0 Hz, 1 -H), 6.88 (1H, s, =CH), 7.53
(2H, d, J = 8.5 Hz, H-2‘, H-6‘), 7.54 (2H, d, J = 9.0 Hz, H-3‘, H-5‘).
(C-6 ), 65.00 (C-2 ), 67.00 (C-3 ), 71.00 (C-4 ), 74.00 (C-5 ), 82.48
13C-NMR (125 MHz, DMSO-d6): δ = 30.89 (N3-CH3), 62.80 (C-6 ),
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
(C-1 ), 122.24 (=CH), 127.56, 128.79, 130.79, 131.00, 140.54 (C-Ar
67.42 (C-2 ), 70.62 (C-3 ), 79.68 (C-4 ), 80.74 (C-5 ), 85.92 (C-1 ),
14

A.I. Khodair, S.B. Bakare, M.K. Awad et al.
Journal of Molecular Structure 1229 (2021) 129805
122.00 (=CH), 123.16, 129.20, 130.08, 131.11, 132.12 (C-Ar and C-5),
162.46 (C-4), 178.78 (C-2). MS: C17 H19 ClN2O6S: m/z: 414 (M+·, 1%).
(E)-5-(Benzylidene)-3-(β-D-galactopyranosyl)-1-methyl-2-
thioxoimidazoliden-4-one (11e): Yield: 0.37 g (97%). Mp: 138-140
survival and values of IC50 were determined using Graph Pad Prism
7.0.
4.7.2. Molecular Docking Studies
°C. IR (KBr): v = 3498 (OH), 1732 (CO), 1388 (CS) cm−1
.
1H-NMR
All the molecular modeling studies were carried out on Intel®
CoreTM i3 CPU, 2.40 GHZ processor, and 3 GB memory with Win-
dows 7 operating system using Molecular Operating Environment
(MOE 2008-10 Chemical Computing Group, Canada) as the compu-
tational software. For the docking studies, the crystal structure of
human cyclin-dependent kinase 2 in complex with recovering was
obtained from the freely accessible Protein data bank (PDB code:
2a4l) [76], verification process was performed by re-docking of the
co-crystallized ligand into the active site using the default settings.
The steroidal derivatives were constructed 2D using ChemBio-office
2015, converted to 3D by builder interface of MOE program, and
then were subjected to energy minimization with MMFF94X force
and the partial charges were automatically calculated. Different
conformers for each compound are imported by systematic con-
formational of the MOE and saved in an mdbdatabase file to be
docked into the active site of the receptor. Visualization for ligand-
receptor interactions was made by Chimera software.
ꢀ
ꢀ
(500 MHz, CD3OD-d4): δ = 3.67 (1H, m, H-5 ), 3.69 (2H, m, H-6 ,
ꢀ
ꢀ
H-6 ’), 3.76 (1H, t, J = 9.5 Hz, 4 -H), 3.95 (3H, s, N3-CH3), 3.97 (1H,
ꢀ
ꢀ
t, J = 10.0 Hz, 3 -H), 4.32 (1H, t, J = 10.0 Hz, 2 -H), 5.74 (1H, d,
2J1’,2’= 10.0 Hz, 1 -H), 6.94 (1H, s, =CH), 7.32 (3H, m, H-Ar), 8.00
ꢀ
(2H, d, J = 8.0, H-Ar). 13C-NMR (125 MHz, CD3OD-d4): δ = 31.83
ꢀ
ꢀ
ꢀ
ꢀ
(N3-CH3), 62.35 (C-6 ), 64.86 (C-2 ), 70.66 (C-3 ), 76.26 (C-4 ),
ꢀ
ꢀ
79.74 (C-5 ), 86.72 (C-1 ), 122.25.00 (=CH), 129.19, 129.56, 130.74,
132.15, 134.08 (C-Ar and C-5), 164.98 (C-4), 182.00 (C-2).
(E)-5-(Methylbenzylidene)-3-(β-D-galactopyranosyl)-1-
methyl-2-thioxoimidazoliden-4-one (11f): Yield: 0.29
g (74%).
Mp: 140-142 °C. IR (KBr): v = 3556 (OH), 1712 (CO), 1394 (CS)
cm−1
.
1H-NMR (500 MHz, CD3OD-d4): δ = 2.46 (3H, s, CH3C6H4),
3.47 (3H, s, N3-CH3), 3.50 (1H, m, 5’-H), 3.55 (2H, m, 6’-H, 6”-H),
3.59 (1H, t, J = 9.5 Hz, 4’-H), 3.62 (1H, t, J = 10.0 Hz, 3’-H), 3.99
2
(1H, t, J = 10.0 Hz, 2’-H), 5.74 (1H, d, J1’,2’= 10.0 Hz, 1’-H), 6.85
ꢀ
(1H, s, =CH), 7.26 (2H, d, J = 8.5 Hz, H-3 , H-5‘), 7.99 (2H, d,
J = 8.0 Hz, H-2‘, H-6‘). 13C-NMR (125 MHz, CD3OD-d4): δ = 30.78
Credit Author Statement
ꢀ
ꢀ
ꢀ
(N1CH3), 36.12 (CH3), 62.34 (C-6 ), 64.54 (C-2 ), 70.62 (C-3 ), 76.27
ꢀ
ꢀ
ꢀ
(C-4 ), 79.80 (C-5 ), 87.00 (C-1 ), 122.00 (=CH), 128.20, 128.90,
129.10, 129.90, 131.10 (C-Ar and C-5), 164.80 (C-4), 185.20 (C-2).
(E)-5-(Methoxybenzylidene)-3-(β-D-galactopyranosyl)-1-
methyl-2-thioxoimidazoliden-4-one (11g): Yield: 0.40 g (97%).
Ahmed I. Khodair: Design, introduction, interpretation of dis-
cussion, results, spectral data, expermental results, writing draft
and English polishing; Safyah B. Bakare: Experimental results and
interpretation of spectral data; Mohamed K. Awad: Computational
calculations, interpretation of discussion and results of computa-
tional calculations data; Mohamed S. Nafie: Biological measure-
ments, interpretation of discussion and results of biological mea-
surements data.
Mp: 92-94 °C. IR (KBr): v = 3450 (OH), 1725 (CO), 1386 (CS) cm−1
.
1H-NMR (500 MHz, CD3OD-d4): δ = 3.41 (3H, s, N3-CH3), 3.58
(1H, m, 5’-H), 3.60 (2H, m, 6’-H, 6”-H), 3.76 (1H, t, J = 10.0 Hz,
4’-H), 3.87 (3H, s, OCH3), 3.95 (1H, t, J = 10.0 Hz, 3’-H), 4.09 (1H,
2
t, J = 10.0 Hz, 2’-H), 5.72 (1H, d, J1’,2’= 10.0 Hz, 1’-H), 6.93 (1H, s,
=CH), 7.03 (2H, d, J = 8.5 Hz, H-2‘, H-6‘), 7.40 (2H, d, J = 8.5 Hz,
H-3‘, H-5‘).
Declaration of Competing Interest
(E)-5-(Chlorobenzylidene)-3-(β-D-galactopyranosyl)-1-
methyl-2-thioxoimidazoliden-4-one (11h): Yield: 0.32 g (82%).
Mp: 120-122 °C. IR (KBr): v = 3420 (OH), 1738 (CO), 1384 (CS)
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared to
influence the work reported in this paper.
cm−1
.
1H-NMR (500 MHz, CD3OD-d4): δ = 3.33 (3H, s, N3-CH3),
ꢀ
ꢀ
ꢀ
3.58 (1H, m, H-5 ), 3.60 (2H, m, H-6 , H-6 ’), 3.76 (1H, t, J = 10.0
Acknowledgements
ꢀ
ꢀ
Hz, 4 -H), 3.95 (1H, t, J = 10.0 Hz, 3 -H), 4.09 (1H, t, J = 10.0
ꢀ
2
ꢀ
Hz, 2 -H), 5.72 (1H, d, J1’,2’= 10.0 Hz, 1 -H), 6.93 (1H, s, =CH),
7.03 (2H, d, J = 9.0 Hz, H-2‘, H-6‘), 7.40 (2H, d, J = 9.0 Hz, H-3‘,
H-5‘). 13C-NMR (125 MHz, CD3OD-d4): δ = 31.82 (N3-CH3), 62.34
Research center (King Saud University) is thanked for carrying
out the measuring of IR, 1H NMR, 13C NMR and MS. Ahmed I. Kho-
dair is grateful for an Alexander von Humboldt-Fellowship.
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
(C-6 ), 67.53 (C-2 ), 70.62 (C-3 ), 72.94 (C-4 ), 79.75 (C-5 ), 86.74
ꢀ
(C-1 ), 120.40 (=CH), 129.32, 129.74, 132.35, 133.72 (C-Ar and C-5),
Supplementary materials
162.42 (C-4), 182.27 (C-2).
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.molstruc.2020.129805.
4.7. Methodology
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