New N-ribosides and N-mannosides of rhodanine derivatives with anticancer activity on leukemia cell line: Design, synthesis, DFT and molecular modelling studies

Article abstract of DOI:10.1016/j.carres.2019.107894

N-ribosylation and N-mannosylation compounds have a great role in compounds activity as anticancer. The reaction of 2-thioxo-4-thiazolidinone (rhodanine) derivatives, as aglycon part, was done with ribofuranose and mannopyranose sugars (glycone part) foll

Full text of DOI:10.1016/j.carres.2019.107894

Carbohydrate Research 487 (2020) 107894
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
New N-ribosides and N-mannosides of rhodanine derivatives with anticancer
activity on leukemia cell line: Design, synthesis, DFT and molecular
modelling studies
a,∗
b
c
d,∗∗
Ahmed I. Khodair , Mohamed K. Awad , Jean-Pierre Gesson , Yaseen A.M.M. Elshaier
b
c
d
a
Chemistry Department, Faculty Science, Kafrelsheikh University, 33516, Kafrelsheikh, Egypt
Theoretical Applied Chemistry Unit (TACU), Chemistry Department, Faculty of Science, Tanta University, Tanta, Egypt
Laboratoire Synthèse et Réactivité des Substances Naturelles, Université de Poitiers, CNRS-UMR 6514, 40 Avenue Du Recteur Pineau, Poitiers F, 86022, France
Organic and Medicinal Chemistry Department, Faculty of Pharmacy, University of Sadat City, 32958, Menoufia, Egypt
A R T I C L E I N F O
A B S T R A C T
Keywords:
N-ribosylation and N-mannosylation compounds have a great role in compounds activity as anticancer. The
reaction of 2-thioxo-4-thiazolidinone (rhodanine) derivatives, as aglycon part, was done with ribofuranose and
mannopyranose sugars (glycone part) followed by deacetylation without cleavage of the rhodanine under acidic
medium. Conformational analysis has been studied using NMR methods (2D, DQF-COSY, HMQC and HMBC). All
final the new deprotected nucleosides were screened against leukemia 1210, and were found to be considerably
less potent (Ic50% 1.4–10.6 μM) than doxorubicin (Ic50% 0.02 μM). Compounds 10d and 10e which contain
ribose moiety have better activity than those with mannose sugar. DFT calculations with B3LYP/6-31 + G (d)
level were used to analyze the electronic and geometric characteristics deduced from the stable structure of the
compounds. The principal quantum chemical descriptors showed a good correlation with the experimental
observations. Rapid Overlay Comparison Similarity (ROCS) study was operated to explain the compounds si-
milarity and to figure out the most important pharmacophoric features.
Rhodanine
Thiazolidinones
Antileukemic activity
ROCS analysis
Molecular modelling
DFT calculations
1
. Introduction
In the recent past, tremendous efforts have been made to develop
drug candidate contains thiazolidinone ring linked to pyridinylquino-
line through ethene part, Fig. 1. In the same rational, 5-benzilidene-3-
ethyl rhodanine (BTR-1) was reported to have wide spectrum antic-
ancer activities with an IC50 value of < 10 μM. BTR-1 contains rho-
danine ring linked to arylidine system, Fig. 1 [20]. However, despite
these activities, a highly active therapeutic compound from this class is
yet to be explored as anticancer agents with less side effects and more
potency. Glycosides of structurally similar heterocyclic systems have
been reported before [23–27]. 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. Computations have become essential to elucidate struc-
tures, properties of molecules, mechanisms and selectivity of reaction
[28]. The density functional theory (DFT) is one of the most popular
theoretical methods used in calculating a great variety of molecular
properties such as molecular structures, vibrational frequencies, che-
mical shifts, non-linear optical (NLO) effects, natural bond orbital
(NBO) analysis, molecular electrostatic potential, frontier molecular
some heterocyclic small molecules as potent anticancer agents. 2-
Thioxo-4-thiazolidinone is one of the privileged scaffolds in drug dis-
covery [1–7] and its derivatives have been proven to be attractive
compounds due to their outstanding biological activities as antic-
onvulsant, antibacterial, antiviral, Hepatitis C Virus (HCV) protease and
antidiabetic agents [8–14]. Recently, substituted 2-thioxo-4-thiazolidi-
nones as rhodanine were investigated for tumor aggregation inhibitor
[
15–17]. In this context, heterocyclic molecules containing thiazolidine
nucleus such as rhodanine and its bioisostere 2,4-thiazolidinedione
(
TZD) [18,19] derivatives have exhibited a broad spectrum of antic-
ancer activity [19,20], Fig. 1. TZDs are implicated in cancer develop-
ment, progression, and metastasis, as Raf/MEK/extracellular signal-
regulated kinase (ERK), Wnt signal transduction pathways [21] and
peroxisome proliferator activated receptors. GSK1059615 is a novel,
ATP-competitive, and reversible PI3Ks inhibitor, Fig. 1 [20,22]. This
∗
Corresponding author.
∗
∗
Corresponding author.
E-mail addresses: khodair2020@yahoo.com (A.I. Khodair), yaseen.elshaier@fop.usc.edu.eg (Y.A.M.M. Elshaier).
https://doi.org/10.1016/j.carres.2019.107894
Received 27 August 2019; Received in revised form 10 December 2019; Accepted 13 December 2019
Available online 14 December 2019
0008-6215/ © 2019 Elsevier Ltd. All rights reserved.

A.I. Khodair, et al.
Carbohydrate Research 487 (2020) 107894
anomeric coupling constants of 4 is a typical for the β-configurated
ribofuranoses (J1',2' = 3.1 Hz). The rotating from nuclear overhauser
effect (NOE) [40–42] between 1′-H at δ 6.58 and 4′-H is an additional
H
proof for β-configuration, and these data are in agreement with those
reported earlier by Gosselin et al. [43] The ribosylation occurred at the
N-site of the 2-thioxo-4-thiazolidinone (1). This was also visible in the
HMBC spectrum where the anomeric proton of 4 showed cross peak to
C-4 (only one rotator about the ribosidic linkage was observed), and no
such correlation to C-5 was shown, indicating for the N-ribosylation and
not the S-ribosylation. Protons bearing carbon were detected in HMQC
1
spectra [44]. The H NMR (CDCl
3
) spectrum of compound 8a showed a
singlet at δ
H
7.69 ppm assigned to the vinyl proton, indicating the
presence of a Z-configuration for the exocyclic double bond. This is in
1
agreement with the H NMR (CDCl
3
) spectrum of 5-((Z)-benzylidene)-3-
methyl-2-thioxo-4-thiazolidinone whose vinyl proton appears at δ
H
H
7
6
.75 ppm [45]. While, the anomeric proton appears as a doublet at δ
.58 ppm (J1',2' = 3.1 Hz), indicating the presence of the β-D-ribofur-
) spectrum of 8a showed a
166.4 and 193.1 ppm assigned to the carbonyl at C-4 and
the thiocarbonyl group at C-2, respectively. These data are also in
1
3
anose moiety [46]. The C NMR (CDCl
3
singlet at δ
C
1
3
Fig. 1. Potential rhodinine derivatives with anticancer activity and our de-
agreement with the C NMR (CDCl ) spectrum of 5-((Z)-hexylidene-4-
3
signed strategy.
oxo-2-thioxothiazolidinyl)-acetic acid [47], since the carbonyl at C-4
appears at δ 165.7 ppm and the thiocarbonyl group at C-2 appears at
c
δ 194.8 ppm, indicating the presence of N-ribosylation. As a chemical
C
orbitals and thermodynamic properties [29–32]. In continuation of our
work on the synthesis of novel nucleosides as potential antiviral, anti-
tumor agents and keeping in mind the biological significance of 2-
thioxo-4-thiazolidinones [33–36]. We hereby report the synthesis, an-
titumor screening and spectroscopy analysis of a series of N- ribosylated
and N- mannosylated bearing 2-thioxo-4-thiazolidinone bases. Ad-
ditionally, we performed the density functional theory to study the
effect of the molecular and electronic structure changes on the biolo-
gical activity of the investigated compounds. ROCS study was operated
to figure out the important features in our compounds and explain their
evidence for the existence of the N-ribosides - not S-ribosides, the re-
moval of the acetyl groups in the acetylated nucleosides 4 and 8a-f
were accomplished with concentrated hydrochloric acid in methanol at
5
0 °C and furnished the corresponding free nucleosides 9 and 10a-f,
respectively. The protected nucleoside 8a and the deprotected nucleo-
side 10a were independently synthesized through another pathway in
quantitative yields via the condensation of 4 and 9, respectively, with
the benzaldehyde (5a) in anhydrous ethanol in the presence of anhy-
drous morpholine at room temperature (Scheme 1).
This series was extended with more sugar moieties such as the
peracetylated mannosyl bromide [48] bearing the 2-thioxo-4-thiazoli-
dinones precursors to examine their potential biological activity.
Treatment of 6a,b,e with 1.1 equivalents of NaH in anhydrous acet-
onitrile furnished the sodium salts of 5-((Z)-arylidene)-2-thioxo-4-
thiazolidinones (11a-c), which in turn were treated with 2,3,4,6-tetra-
O-acetyl-α-D-mannopyranosyl bromide (12) to afford protected man-
nonucleosides 13a-c. Removal of the acetyl groups from the glycon
moiety of 13a,b with a solution of conc. HCl/MeOH at 50 °C for 2 h
furnished 5-((Z)-arylidene)-3-(β-D-mannopyranosyl)-2-thioxo-4-thiazo-
lidinones (14a,b), indicating the presence of N-mannosylation. The
structures of 13a-c and 14a,b were established and confirmed by ele-
3
D-QSAR. The design strategy, as showed in Fig. 1, was elaborated
through the following modifications: replacement of arylidine ring by
substituted arylidine ring; using rhodanine ring as in BTR-1 and finally,
installing sugar moiety to improve drug pharmacokinetics.
2
. Results and discussion
The present work describes the synthesis of new series of 5-((Z)-
arylidene)-3-(2′,3′,5′-tri-O-acetyl-β-D-ribofuranosyl)-2-thioxo-4-thiazo-
lidinones (8a-f), 5-((Z)-arylidene)-3-(β-D-ribofuranosyl)-2-thioxo-4-
thiazolidinones (10a-f), 5-((Z)-arylidene)-3-(2′,3′,4′,6′-tetra-O-acetyl-β-
D-mannopyranos-yl)-2-thioxo-4-thiazolidinones (13a-c) and 5-((Z)-ar-
ylidene)-3-(β-D-mannopyranosyl)-2-thioxo-4-thiazolidinones (14a,b)
via new synthetic strategies. The silylation of the nucleoside base 1 was
accomplished with bis(trimethylsilyl)acetamide (BSA) in anhydrous
MeCN at 70–80 °C, and furnished the trimethylsilylated derivative 2.
Derivative 2 was condensed, devised by Vorbrüggen et al. [37], with
1
13
mental analyses and spectral data (IR, H NMR, C NMR and MS). The
mass spectrum of 13b showed a molecular ion peak at m/z 581, while
1
the H NMR (CDCl
3
) spectrum of compound 13b showed a singlet at δ
H
7.68 ppm assigned to the vinyl proton, indicating the presence of a Z-
configuration for the exocyclic double bond. This is in agreement with
1
the H NMR (DMSO‑d
6
) spectrum of 6b whose vinyl proton appears at
1
,2,3,5-tetra-O-acetyl-β-D-ribofuranose (3) in the presence of tri-
methylsilyl trifluoromethanesulfonate (TMSOTf) as catalyst at
0–80 °C for 60 min. The protected nucleoside 4 was isolated by silica
δ
H
H
7.63 ppm [38]. While, the anomeric proton appears as a doublet at
6.35 ppm (J1’,2’ = 9.4 Hz), indicating the presence of the β-D-man-
) spectrum of 13b
166.1 and 194.2 ppm assigned to the carbonyl at
C-4 and the thiocarbonyl group at C-2, respectively. These data are also
a
δ
1
3
7
nopyranose moiety [49]. The C NMR (CDCl
3
gel column chromatography in 77% yield. On the other hand and under
the same above conditions, the nucleoside bases 6a-f, were prepared
form the direct condensation of 1 with the appropriate aromatic alde-
hydes (5a-f) according to our previous reported procedure [38]. Sily-
lation of nucleoside 6a-f with BSA affords the trimethylsilylated deri-
vatives 7a-f which were coupled directly with 3 to give the protected
ribonucleosides 8a-f in high yields. The structures of 4 and 8a-f were
established and confirmed by elemental analyses and spectral data (IR,
showed a singlet at δ
C
1
3
in agreement with the C NMR (DMSO‑d ) spectrum of 6b, since the
6
carbonyl at C-4 appears at δ 169.7 ppm and the thiocarbonyl group at
c
C-2 appears at δ 196.0 ppm [38], indicating the presence of N-man-
C
nosylation (Scheme 2). Furthermore, the heteronuclear spectra (HMQC,
3
DFQ-COSY) of 14a,b showed
JC,H correlation between C-4 and 1′-H,
which is an additional proof for N-mannosylation.
3. Biological screening
1
13
H NMR, C NMR and MS). The absence of signal for NH and the
−1
presence of signal for the thiocarbonyl group at vmax 1210-1240 cm
were characterized the IR absorption spectra of 4 and 8a-f. The proton
spin systems were identified from DQF-COSY [39] spectra. The
The target compounds 10a-f and 14a-b were subjected to anticancer
2

A.I. Khodair, et al.
Carbohydrate Research 487 (2020) 107894
Scheme 1. Synthesis of the target compounds 9 and 10a-f.
against leukemia-1210 using reported method [50]. The Ic50% for all
compounds was determined and calculated using doxorubicin as stan-
dards, Table 1. All compounds exhibited Ic50% in the range
derivatives not mannosyl derivatives.
4
. Qantum chemical calculations
The quantum chemical methods and molecular modelling techni-
1
0
.4–12.0 μM in comparison to the standard drug doxorubicin (Ic50%
.02 μM). Compounds 14a and 14b were better in activity
(
(
Ic50% = 4.5, 2.3 μM, respectively) than their analogs 10a, and 10b
ques are able to define a large number of molecular quantities char-
acterizing the reactivity, shape, and binding properties of a complete
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 en-
ergies obtained from the calculations of the investigated compounds are
shown in Fig. 2.
Ic50% = 12.0, 5.2 μM, respectively) indicating that mannose moiety
improved the activity rather than ribose ring. Among the ribosyl deri-
vatives, compound 10d was the most potent one (Ic50% = 1.4 μM)
then 10e (Ic50% = 1.6 μM) followed by 10b and 10f (Ic50% = 5.2,
6
.3 μM respectively). Finally, compounds 10c, and 10a were the least
derivatives in activity (Ic50% = 10.6, 12.0 μM, respectively). This
pattern indicating presence of electron with drawing group capable for
formation of hydrogen bond enhance the compounds activity. More-
over, these values of compounds describe that the aryl ring has a role in
activity than the sugar part.
We started our calculations to make a comparison between Z- and E-
forms for nucleosides and many sides and the calculations showed that
the nucleosides and manosides are more stable in the Z-form than E-
form, by about 0.012 au. Also, it was shown from the calculations that
they are in β-forms with higher stability than α-form by about 0.008 au,
which is in a good agreement with the experimental observations. So,
we performed DFT calculations on the stable structures of Z-nucleosides
General screening showed that mannosyl series is more active but
among all compounds, the ribosyl compounds are more potent. And
according to drug discovery strategy, if we will go to synthesize new
derivatives and continue in this project, we will focus on ribosyl
3

A.I. Khodair, et al.
Carbohydrate Research 487 (2020) 107894
Scheme 2. Synthesis of the target compounds 13a-c and 14a,b.
Table 1
compounds could react as electrophiles (electron acceptor), Table 2.
The electrophilicity is the descriptor of reactivity and is sufficient to
describe the toxicity of the molecules. It also provides the direct re-
lationship between the rates of reactions and the ability to identify the
function or capacity of an electrophile and the electrophilic power of
the compounds. It was shown from the calculations that the compounds
Antitumor activity of 5-((Z)-arylidene)-3-(β-D-ribofuranosyl)-2-thioxo-4-thia-
zolidinones (10a-f), and 5-((Z)-arylidene)-3-(β-D-mannopyranosyl)-2-thioxo-4-
thiazolidinones (14a,b) against leukemia-1210.
a
Compound
Ar
IC50 (μM) cellules L-1210
1
1
1
1
1
1
1
1
0a
0b
0c
0d
0e
0f
C
6
H
5
12
1
0d and 10e have high electrophilicity indices (6.908 and 6.509 eV),
4-MeOC
6
H
4
5.2
10.6
1.4
1.6
6.3
4.5
2.3
0.02
respectively, which probably enhance their biological activities and
agree well with the experimental observations.
2 6 3
2,4-Cl C H
2-HO-3-MeOC
2-Thienyl
2-Furyl
6 3
H
Also, experimentally, the unsubstituted phenyl moiety, compound
1
0a, has the lowest biological activity amongst the nucleosides com-
4a
4b
6 5
C H
pounds, which could be explained from the calculated quantum che-
mical parameters. The calculations showed that the unsubstituted
phenyl moiety decreases the energy of the HOMO, the dipole moment
and electrophilicity index while increases the energy gap which means
decreasing the reactivity of compound 10a and accordingly decreases
its biological activity. This is in a good agreement with the experi-
mental data.
6 4
4-MeOC H
Doxorubicin
a
5
0% Inhibitory concentration: molar concentration of compound that cause
5
0% inhibition for cell growth.
and manosides in the β –forms.
The experimental data showed that the presence of dichloro-sub-
stituent at the phenyl moiety of the nucleoside, compound 10c, showed
a low biological activity. Surprisingly, the calculations showed that the
dichloro-substituent increases the energy of HOMO (−4.262 eV),
which is the donor part of the molecule, increases the softness, de-
creasing the energy gap between HOMO-LUMO (2.345 eV), which is
probably more favourable for the reactivity towards the enzyme, the
decreasing of the chemical potential, electronegativity and electro-
philicity mean increasing the reactivity of the molecule and accordingly
increases the biological activity, which is in contradictory with the
experimental observations, Table 1.
It was found from the calculations that the many side compounds,
14a,b are less reactive than the nucleoside compounds 10d,e which
could be shown from the decreasing of the HOMO energies (−6.615,-
6.462 eV), respectively, and increasing the LUMO energies (−2.662,-
2.498 eV), respectively, Table 1, which is in a good agreement with the
experimental observations. Also, increasing the energy gap between
HOMO-LUMO of manosides (3.953, 3.964 eV), respectively, leads to
increase its stability and accordingly decreasing its biological activity.
-
1
Also, it has lower softness (0.506 and 0.505 eV ), respectively, and
electrophilicity values (5.443, 5.063), respectively, than those of nu-
cleosides which are probably responsible for the decreasing its biolo-
gical activity.
The presence of 2-hydroxy-3-methoxy, compound 10d, and thienyl
substituent, compound 10e, in the α-position of the vinyl moiety of the
nucleosides compounds showed a higher biological activity than that
for the rest of the investigated compounds, which could be explained
from the calculated quantum chemical parameters. The calculations
showed that the presence of 2-hydroxy-2-methoxy and thienyl sub-
stituents, compounds 10d and 10e, decrease the energy of the LUMO
5. Frontier molecular orbitals
The HOMO and LUMO levels are very common quantum chemical
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
(
−3.159 and −3.012 eV), respectively, which means that these
4

A.I. Khodair, et al.
Carbohydrate Research 487 (2020) 107894
Fig. 2. The optimized molecular structures, charge density distributions (HOMO and LUMO) for the investigated compounds.
5

A.I. Khodair, et al.
Carbohydrate Research 487 (2020) 107894
Table 2
The calculated quantum chemical parameters obtained from DFT/B3LYP/6-31 + G (d) of the investigated compounds.
−
1
Compound
EHOMO(eV)
E
LUMO(eV)
ΔE(eV)
DM(D)
IP(eV)
EA(eV)
η(eV)
σ(eV
)
μ(eV)
χ(eV)
ω
Ea.u.
IC50μM
1
1
1
1
1
1
1
1
0a
0b
0c
0d
0e
0f
−6.515
−6.221
−4.262
−6.521
−6.342
−6.231
−6.615
−6.462
−2.991
−2.863
−1.917
−3.159
−3.012
−2.989
−2.662
−2.498
3.524
3.358
2.345
3.362
3.330
3.242
3.953
3.964
4.370
8.371
5.919
5.513
4.873
5.338
6.974
8.405
6.515
6.221
4.262
6.521
6.342
6.231
6.615
6.462
2.991
2.863
1.917
3.159
3.012
2.989
2.662
2,498
1.762
1.679
1.173
1.681
1.665
1.621
1.977
1.982
0.568
0.596
0.853
0.595
0.600
0.617
0.506
0.505
4.753
4.542
3.090
4.840
4.677
4.610
4.639
4.480
−4.753
−4.542
−3.090
−4.840
−4.677
−4.610
−4.639
−4.480
6.411
6.143
4.070
6.968
6.569
6.555
5.443
5.063
−1807.856
−1922.383
−2726.877
−1997.508
−2128.595
−1805.640
−1563.532
−1678.059
12
5.2
10.6
1.4
1.6
6.3
4.5
2.3
4a
4b
Fig. 2. It was shown from the investigated compounds that the HOMO
levels, which could be reacted as a nucleophile (hydrogen bond ac-
ceptor) with the biological target, is mainly localized on the whole
molecule except for the trihydroxy six and five membered rings. But in
the case of compound 10c, the dichlorophenyl moiety will slightly
contribute in 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 except for trihydroxy five and six
membered rings. The calculations showed that charge transfer may
occur from the nucleophilic sites to the electrophilic part of the same
molecules.
BTR1 with BTR. The thiazolidindion ring adopted perpendicular posi-
tion to same ring with BTR1, Fig. 3 (E).
Considering the Potent inhibitor of PI 3-kinase
α (PI3Kα)
GSK1059615 as a query, it color shape has 4 rings, 4 acceptors and one
donor. The compounds represented high similarity to query
GSK1059615 in their color shape and volume. The sugar moiety
adopted as a ring and as donor/acceptor descriptor (Fig. 4 B). Both
compounds 10d (Figs. 4C) and 14b (Fig. 4 D) adopted a certain 3D
overlay to GSK1059615.
The second output of ROCs analysis is Tanimoto scores which var-
ious aspect of that alignment. The two core scoring methods are Shape
Tanimoto (Tanimoto coefficient) and Color Tanimoto. Tanimoto Combo
is the sum of those two independent components (Shape and Color
Tanimoto). Shape Tanimoto represents the shared volume and mis-
match volume and has scale from 0 to 1. Color Tanimoto is the dis-
tribution of chemical features in 3D (also scale from 0 to 1), Table 3.
The scores are computed and the process is repeated to each con-
formation of the query molecules (BTR1 and GSK1059615) and each
conformation for the database molecule, Table 3. Considering BTR1 as
a query, compounds 10a, 10c have high Tanimoto Combo score more
than GSK1059615 then compounds 10b, 10d, 14b, 10e, 10f, and 14a
respectively. However, in the case of GSK1059615 as a query, com-
pound 10d has high score than BTR1 then compounds 10e, 10f, 14a,
It is concluded from FMOs that the effect of substituents on the
phenyl moiety plays an important role to enhance the affinity of the
tested compounds towards the target enzymes.
6
. Molecular modelling
6.1. ROCS analysis [51–53]
ROCS is a computational method that used to predict similarity
between compounds based on their three dimensional. ROCS analysis
requires a) query molecules and here are BTR1 and GSK1059615; b) the
database molecules and here are our synthesized compounds. The out
puts from ROCs analysis are the overly between the query and database
molecules as visualized by vROCS and VIDA applications. The visuali-
zation of the query includes different descriptors as shape atoms, shape
counter, and color atoms labels. All compounds exhibited high simi-
larity in their ROCs analysis and all of them (except 10a) illustrated
high potency more than query BTR1. It's clear that due to the glycoside
moiety, Table 3.
1
0a, 10c, 14b, and 10b, respectively.
7. Structure activity relationship
The sugar moieties that linked through glycoside linkage have im-
portant roles. Their rules are not only to improve compounds phar-
macokinetics but also it participated in compounds features as an im-
portant pharmacophore. The ribose derivatives have better in activity
more than mannose analogies. This could be due the pose of thiazoli-
dinone thione ring, Fig. 5. In compound 14b, it is easier to form in-
tramolecular HB which forces the structure to be more rigid that hinder
compounds flexibility to adopt a better conformer inside the amino acid
clefts in the receptor. Un-substituted aryl ring or presence of EDG
(electron donating group) is better than those with EWG (electron
withdrawal group) According to Ic50% values and Tanimoto analysis;
the designed compounds demonstrated high similarity to BTR1.
The color shape of query BTR1, illustrated 2 rings, 3 donors, and 2
acceptors, Fig. 3 (A). Compounds 10a, 10b, 10c, 14b showed high si-
milarity in color and shape to BTR1, Fig. 3 (B). Similarly, the standard
GSK1059615 has similarity to BTR1 query, Fig. 3 C. However, com-
pounds 10e and 10f adopted a unique alignment. Both compounds
overlay with BTR1 as query in which sugar part acts as ring and 2 ac-
ceptors, Fig. D. This representation represents the importance of ribose
which has quantified more than receptors in addition to their known
polarity. Finally, Compound 14a has a unique and specific pose with
Table 3
Tanimoto scores for synthesized compounds, and lead compounds.
Comp.
Tanimoto Combo
Shape Tanimoto
Color Tanimoto
Tanimoto Combo
Shape Tanimoto
Color Tanimoto
GSK1059615
1.004
0.905
2
0.566
0.6450
1
0.566
0.260
1
2
1
1
1
0d
0.790
0.78
0.617
0.599
0.579
0.564
0.550
0.533
0.524
0.496
0.460
0.173
0.181
0.150
0.149
0.145
0.158
0.150
0.130
0.136
BTR-I
1
1
1
1
1
1
1
0e
0f
0.790
0.785
0.656
1.03
0.5560
0.5640
0.5100
0.698
0.679
0.6130
0.667
0.234
0.221
0.145
0.333
0.333
0.255
0.307
0.729
0.713
0.695
0.691
0.674
0.626
0.596
4a
0a
0c
4b
0b
1.02
0.868
0.974
6

A.I. Khodair, et al.
Carbohydrate Research 487 (2020) 107894
Fig. 3. A) Colour and shape of BTR1 as query; B) Compounds 10a-10c, and 14b in color and shape to BTR1; C) Both GSK1059615 and BTR1 (query); D) Compounds
1
0e and 10f with BTR1 as query; E) 14a with BTR1 with specific pose; 14a with BTR1 color with specific pose. (For interpretation of the references to color in this
figure legend, the reader is referred to the Web version of this article.)
In conclusion, we have described the successful synthesis of ribo-
nucleosides and mannonucleosides of 2-thioxo-4-thiazolidinone deri-
vatives and the confirmation of their most stable conformation by NMR
spectroscopy. The ribonucleosides 10a-f and the mannonucleosides
skeleton) is better in activity than mannose (hexoses). The aryl part is
better to be with EDG capable to form HB with receptors.
1
4a,b were screened against leukemia-1210, and were found to be
8. Experimental section
considerably less active as compared to doxorubicin (Table 1). The
antiviral and the further antitumor activities of the new prepared
compounds are under investigation and will be reported in the due
time. The nucleoside bases 1 and 6 can be utilized as starting materials
for the synthesis of other carbohydrate derivatives as deoxy, amino and
azido nucleosides. The electronic and geometric structures were de-
duced from DFT calculations with B3LYP/6-31 + G (d) level to analyze
the stable structure of the compounds. The quantum chemical para-
meters obtained from the calculations showed a good correlation with
the experimental observations. ROCS analysis showed that sugar part is
important molecular descriptor. 3D-QSAR showed ribose (furnaose
General: Melting points were determined on a Büchi apparatus and
are uncorrected. TLC was carried out on aluminum sheet silica gel 60
F
254 (Merck), and detected by short UV light. IR spectra were obtained
1
as potassium bromide pellets using a Pye Unicam spectrometer 1000. H
1
3
NMR and C NMR spectra were measured on a Bruker Advance DPX
300 MHz spectrometers in DMSO‑d
6
or CDCl using TMS as internal
3
standard. Chemical shifts are given in ppm and J values in Hz.
Analytical data were obtained using a C,H,N Elemental analyzer Carlo
Erba 1106. Mass spectra were recorded by EI on a Varian MAT 112
spectrometer and FAB on a Kratos MS spectrometer.
7

A.I. Khodair, et al.
Carbohydrate Research 487 (2020) 107894
Fig. 4. A) Colour and shape of GSK10596151 as
query; B) Color and shape of all compounds
except 10b and 14b; C) compound10dshape
with standard volume; D) compound 14b shape
with standard volume. (For interpretation of the
references to color in this figure legend, the
reader is referred to the Web version of this ar-
ticle.)
1
8
.1. 3-(2′,3′,5′-Tri-O-acetyl-β-D-ribofuranosyl)-2-thioxo-4-thiazolidinone
4)
(CO), 1238 cm−1 (CS); H NMR (CDCl
): δ 2.09 (s, 3H, Ac), 2.10 (s, 3H,
3
(
Ac), 2.11 (s, 3H, Ac), 3.95 (s, 2H, 5-H), 4.19–4.45 (m, 3H, 4′-H, 5′-H,
5
″-H), 5.52 (dd, J = 6.7, 7.0 Hz, 1H, 3′-H), 5.85 (dd, J = 3.3, 6.6 Hz,
13
2
-Thioxo-4-thiazolidinone (1) (665 mg, 5 mmol) was suspended in
1H, 2′-H), 6.40 (d, J = 3.2 Hz, 1H, 1′-H); C NMR (CDCl ): δ 20.74,
3
anhydrous acetonitrile (25 ml) and BSA (1.25 ml, 5 mmol) was added,
and the reaction mixture was heated at 70–80 °C for 30 min. The
20.81, 20.85 (3 Ac), 35.02 (C-5), 63.50 (C-5′), 70.04 (C-3′), 71.26 (C-
2′), 80.01 (C-4′), 84.30 (C-1′), 169.98, 170.06, 171.20 (3 Ac), 174.00
+
1
,2,3,.5-tetra-O-acetyl-α-D-ribofuranose (3) (1.75 g, 5 mmol) dissolved
(C-4), 202.15 (C-2); MS, m/z
=
391 (M ); Anal. Calcd. for
in anhydrous acetonitrile (25 ml) was added to the reaction mixture via
C
14
H
17NO
8
S (391.42): C, 42.96; H, 4.38; N, 3.58. Found: C, 43.17; H,
2
a cannula. Finally TMSOTf (1.00 ml, 5 mmol) was added, and the re-
4.60; N, 3.42.
action mixture was heated at 70–80 °C for 60 min. Saturated NaHCO
3
was added to quench the reaction and the resulting mixture extracted
8
.2. 5-((Z)-Arylidene)-3-(2′,3′,5′-tri-O-acetyl-β-D-ribofuranosyl)-2-thioxo-
-thiazolidinone (8a-f)
with CH Cl . The combined organic fractions were washed with satu-
2
2
4
rated NaCl solution, dried over MgSO , filtered, and evaporated under
4
reduced pressure till dryness. The product was purified by flash chro-
matography (eluent 30–50%, diethyl ether/petroleum ether, 40–60 °C)
to afford 3.00 g (77%) of 4 as yellow foams. IR (KBr): v 1746 cm−1
Method A: General Procedure: 5-((Z)-Arylidene)-2-thioxo-4-thiazoli-
dinones (6a-f) (5 mmol) were suspended in anhydrous acetonitrile
(
25 ml) and BSA (1.25 ml, 5 mmol) was added, and the reaction
Fig. 5. 3D representation of compounds 14b, 10b in which compound 14b more available to form intrameolecular HB.
8

A.I. Khodair, et al.
Carbohydrate Research 487 (2020) 107894
mixture was heated at 70–80 °C for 30 min. The 1,2,3,5-tetra-O-acetyl-
α-D-ribofuranose (3) (1.75 g, 5 mmol) dissolved in anhydrous acetoni-
trile (25 ml) was added to the reaction mixture via a cannula. Finally,
TMSOTf (1.00 ml, 5 mmol) was added, and the reaction mixture was
2.12 (s, 3H, Ac), 3.86 (s, 3H, OCH
3
), 4.20 (dd, J = 6.3, 11.6 Hz, 1H, 4′-
H), 4.32 (ddd, J = 2.9, 7.2, 10.6 Hz, 1H, 5′-H), 4.54 (dd, J = 2.9,
11.6 Hz, 1H, 5″-H), 5.68 (dd, J = 6.4, 7.1 Hz, 1H, 3′-H), 5.92 (dd,
J = 3.1, 6.5 Hz, 1H, 2′-H), 6.58 (d, J = 2.9 Hz, 1H, 1′-H), 6.58 (s, 1H,
heated at 70–80 °C for 60 min. Saturated NaHCO
3
was added to quench
Cl . The
combined organic fractions were washed with saturated NaCl solution,
OH), 7.00, 7.46 (2d, J = 8.50 Hz, 4H, Ar–H), 7.68 (s, 1H, =CH); MS,
+
the reaction and the resulting mixture extracted with CH
2
2
m/z = 525 (M ); Anal. Calcd. for C22
H23NO10
2
S (525.55): C, 50.28; H,
4.41; N, 2.67. Found: C, 50.36; H, 4.62; N, 2.60.
dried over MgSO , filtered, and evaporated to dryness. The products
4
were purified by flash chromatography (eluent 30–50%, diethyl ether/
petroleum ether, 40–60 °C) to afford the title compounds 8a-f in good
yields.
8.7. 5-((Z)-2-Thienylidene)-3-(2′,3′,5′-tri-O-acetyl-β-D-ribofuranosyl)-2-
thioxo-4-thiazolidinone (8e)
−
1
8
.3. 5-((Z)-Benzylidene)-3-(2′,3′,5′-tri-O-acetyl-β-D-ribofuranosyl)-2-
Yield 2.00 g (82%); yellow foams; IR (KBr): ν 1747 cm
(CO),
−1
1
thioxo-4-thiazolidinone (8a)
1230 cm (CS); H NMR (CDCl
3
): δ 2.10 (s, 3H, Ac), 2.11 (s, 3H, Ac),
2
.12 (s, 3H, Ac), 4.23–4.52 (m, 3H, 4′-H, 5′-H, 5″-H), 5.67 (dd, J = 6.5,
−
1
Yield 2.00 g (83%); yellow foams; IR (KBr): v 1748 cm
(CO),
7.0 Hz, 1H, 3′-H), 5.95 (dd, J = 3.0, 7.3 Hz, 1H, 2′-H), 6.55 (d,
J = 3.1 Hz, 1H, 1′-H), 7.20 (dd, J = 3.7, 5.0 Hz, 1H, 4″-H), 7.42 (d,
J = 3.7 Hz, 1H, 3″-H), 7.74 (d, J = 5.0 Hz, 1H, 5″-H), 7.85 (s, 1H,
−
1
1
1
2
232 cm (CS); H NMR (CDCl ): δ 2.11 (s, 3H, Ac), 2.12 (s, 3H, Ac),
3
.13 (s, 3H, Ac), 4.25 (dd, J = 6.2, 11.7 Hz, 1H, 4′-H), 4.34 (ddd,
1
3
J = 2.8, 7.3, 10.5 Hz, 1H, 5′-H), 4.53 (dd, J = 3.0, 11.7 Hz, 1H, 5″-H),
=CH); C NMR (CDCl ): δ 20.69, 20.74, 20.02 (3 Ac), 63.24 (C-5′),
3
5
.67 (dd, J = 6.3, 7.0 Hz, 1H, 3′-H), 5.96 (dd, J = 3.2, 6.5 Hz, 1H, 2′-
70.44 (C-3′), 72.10 (C-2′), 79.59 (C-4′), 88.11 (C-1′), 119.30 (=CH),
H), 6.58 (d, J = 3.1 Hz, 1H, 1′-H), 7.48 (m, 5H, Ar–H), 7.69 (s, 1H,
126.42, 129.32, 133.84, 134.75, 137.97 (C–Ar, C-5), 166.52 (C-4),
1
3
+
=
CH); C NMR (CDCl
3
): δ 20.26, 20.30, 20.58 (3 Ac), 62.84 (C-5′),
169.79, 169.86, 170.86 (3 Ac), 192.71 (C-2); MS, m/z = 485 (M );
7
1
1
0.10 (C-3′), 71.71 (C-2′), 79.25 (C-4′), 87.65 (C-1′), 121.12 (=CH),
29.24, 130.54, 130.86, 132.92 (C–Ar), 133.69 (C-5), 166.40 (C-4),
Anal. Calcd. for C19
H
19NO
8
S (485.55): C, 47.00; H, 3.94; N, 2.88.
3
Found: C, 47.18; H, 4.20; N, 2.67.
+
69.26, 169.43, 170.44(3 Ac), 193.11 (C-2); MS, m/z = 479 (M );
Anal. Calcd. for C21
H21NO
8
S (479.53): C, 52.60; H, 4.41; N, 2.92.
2
Found: C, 52.84; H, 4.67; N, 2.80.
8.8. 5-((Z)-2-Furylidene)-3-(2′,3′,5′-tri-O-acetyl-β-D-ribofuranosyl)-2-
thioxo-4-thiazolidinone (8f)
8
.4. 5-((Z)-4-Methoxybenzylidene)-3-(2′,3′,5′-tri-O-acetyl-β-D-ribofuranosyl)-
−
1
2
-thioxo-4-thiazolidinone (8b)
Yield 2.00 g (85%); yellow foams; IR (KBr): v 1748 cm
(CO),
−1
1
1
238 cm (CS); H NMR (CDCl ): δ 2.10 (s, 3H, Ac), 2.11 (s, 3H, Ac),
3
Yield 2.18 g (86%); yellow solid; mp 87–89 °C; IR (KBr): v
2.12 (s, 3H, Ac), 4.23–4.52 (m, 3H, 4′-H, 5′-H, 5″-H), 5.67 (t,
J = 6.96 Hz, 1H, 3′-H), 5.95 (dd, J = 3.03, 7.32 Hz, 1H, 2′-H), 6.55 (d,
J = 3.0 Hz, 1H, 1′-H), 6.68 (dd, J = 3.7, 5.0 Hz, 1H, 4″-H), 7.23 (d,
−
1
−1
1
1
2
746 cm (CO), 1230 cm (CS); H NMR (CDCl ): δ 2.08 (s, 3H, Ac),
3
.10 (s, 3H, CH
3
), 2.12 (s, 3H, Ac), 3.87 (s, 3H, OCH ), 4.21 (dd,
3
J = 6.2, 11.7 Hz, 1H, 4′-H), 4.30 (ddd, J = 2.8, 7.3, 10.5 Hz, 1H, 5′-H),
J = 3.7 Hz, 1H, 3″-H), 7.40 (d, J = 5.0 Hz, 1H, 5″-H), 7.85 (s, 1H,
+
4
.51 (dd, J = 2.8, 11.6 Hz, 1H, 5″-H), 5.66 (dd, J = 6.5, 7.1 Hz, 1H, 3′-
=CH); MS, m/z = 469 (M ); Anal. Calcd. for C19
H
19NO
9
S (469.49):
2
H), 5.93 (dd, J = 3.2, 6.5 Hz, 1H, 2′-H), 6.57 (d, J = 2.8 Hz, 1H, 1′-H),
C, 48.61; H, 4.08; N, 2.98. Found: C, 48.86; H, 4.35; N, 2.79.
1
3
7
.00, 7.45 (2d, J = 8.9 Hz, 4H, Ar–H), 7.66 (s, 1H, =CH); C NMR
Method B: To a mixture of the protected nucleoside 4 (391 mg,
1 mmol), anhydrous morpholine (0.09 g, 1 mmol) and anhydrous
ethanol (10 ml) was added benzaldehyde (0.11 g, 1 mmol). The mixture
was stirred until the starting material was consumed (12 h; TLC). The
reaction mixture was neutralized with HCl/MeOH. After stirring for
5 min, the solution was evaporated in vacuo and the residue was pur-
ified by flash chromatography (eluent 30–50%, diethyl ether/petro-
leum ether, 40–60 °C) to afford 412 mg (86%) of 8a as yellow solid.
(
CDCl
3
): δ 20.51, 20.80 (3 Ac), 55.58 (OCH ), 63.08 (C-5′), 70.26 (C-
3
3
1
1
′), 71.96 (C-2′), 79.36 (C-4′), 87.82 (C-1′), 115.03, 118.14, 125.85,
32.93, 134.03, 161.97 (=CH, C–Ar, C-5), 166.76 (C-4), 169.47,
+
69.65, 170.40 (3 Ac), 193.35 (C-2); MS, m/z = 509 (M ); Anal. Calcd.
for C22
H23NO
9
S (509.55): C, 51.86; H, 4.55; N, 2.75. Found: C, 51.98;
2
H, 4.80; N, 2.62.
8
.5. 5-((Z)-2,3-Dichlorobenzylidene)-3-(2′,3′,5′-tri-O-acetyl-β-D-
ribofuranosyl)-2-thioxo-4-thiazolidinone (8c)
8
.9. 3-(β-D-Ribofuranosyl)-2-thioxo-4-thiazolidinone (9)
−
1
Yield 2.11 g (77%); yellow oil; IR (KBr): v 1748 cm
(CO),
−
1
1
1
2
225 cm (CS); H NMR (CDCl
3
): δ 2.11 (s, 3H, Ac), 2.12 (s, 3H, Ac),
The protected nucleoside 4 (1 mmol) was suspended in MeOH
.13 (s, 3H, Ac), 4.27 (dd, J = 6.2, 11.7 Hz, 1H, 4′-H), 4.32 (ddd,
(15 ml), and concentrated HCl (0.5 ml) was added. The reaction mix-
ture was heated for 2 h at 50 °C. To the resulting solution was added an
J = 2.8, 7.3, 10.5 Hz, 1H, 5′-H), 4.54 (dd, J = 2.9, 11.9 Hz, 1H, 5″-H),
−
5
.65 (dd, J = 6.2, 6.5 Hz, 1H, 3′-H), 5.93 (dd, J = 3.0, 6.5 Hz, 1H, 2′-
ion exchange resin (Amberlite IR-120, OH -form), previously washed
H), 6.55 (d, J = 2.9 Hz, 1H, 1′-H), 7.28–7.52 (m, 3H, Ar–H), 7.98 (s,
with MeOH. After stirring for 5 min, the solution was filtered and
1
3
1
H, =CH); C NMR (CDCl
3
): δ 20.45, 20.48, 20.78 (3 Ac), 62.82 (C-
evaporated in vacuo and the residue was purified by flash chromato-
5
′), 70.07 (C-3′), 71.90 (C-2′), 79.36 (C-4′), 87.90 (C-1′), 124.56
graphy (eluent 0–5%, CHCl /MeOH) to afford 212 mg (80%) of 9 as
3
−1
(
=CH), 127.92, 128.28, 129.85, 130.02, 130.56, 136.96, 137.23 (C–Ar,
pale yellow solid; mp 143–145 °C; IR (KBr): v 3441 cm
(OH),
−1
−1
1
C-5), 166.00 (C-4), 169.47, 169.68, 170.67 (3 Ac), 192.32 (C-2); MS,
1651 cm (CO), 1239 cm (CS); H NMR (CD
3
OD-d
4
): δ 3.49 (s, 2H,
+
m/z = 548 (M ); Anal. Calcd. for C21
H19Cl
2
NO
S
8 2
(548.41): C, 45.99;
5-H), 3.62 (dd, J = 4.4, 13.3 Hz, 2H, 5′-H, 5″-H), 3.85 (dd, J = 4.1,
H, 3.49; N, 2.55. Found: C, 46.22; H, 3.65; N, 2.38.
14.0 Hz, 1H, 4′-H), 4.07 (dd, J = 5.5, 8.6 Hz, 1H, 3′-H), 5.12 (dd,
1
3
J = 5.2, 5.3 Hz, 1H, 2′-H), 5.73 (d, J = 5.3 Hz, 1H, 1′-H); C NMR
8
.6. 5-((Z)-2-Hydroxy-3-methoxybenzylidene)-3-(2′,3′,5′-tri-O-acetyl-β-
(DMSO‑d ): δ 43.51 (C-5), 61.82 (C-5′), 73.02 (C-3′), 81.26 (C-2′),
6
D-ribofuranos-yl)-2-thioxo-4-thiazolidinone (8d)
87.14 (C-4′), 90.12 (C-1′), 174.75 (C-4), 192.87 (C-2); MS, m/z = 265
+
(
M
); Anal. Calcd. for C
8
H
11NO
5
S (265.31): C, 36.22; H, 4.18; N, 5.28.
2
−
1
Yield 1.84 g (70%); yellow foams; IR (KBr): v 1750 cm
(CO),
),
Found: C, 36.46; H, 4.41; N, 5.17.
−
1
1
1
226 cm (CS); H NMR (CDCl
3
): δ 2.06 (s, 3H, Ac), 2.09 (s, 3H, CH
3
9

A.I. Khodair, et al.
Carbohydrate Research 487 (2020) 107894
8
.10. 5-((Z)-Arylidene)-3-(β-D-ribofuranosyl)-2-thioxo-4-thiazolidinone
J = 5.8, 5.9 Hz, 1H, 3′-H), 4.72 (dd, J = 4.2, 5.6 Hz, 2′-H), 6.28 (d,
(
10a-f)
J = 4.0 Hz, 1H, 1′-H), 6.86–7.16 (m, 3H, Ar–H), 7.92 (s, 1H, =CH);
+
MS, m/z = 399 (M ); Anal. Calcd. for C16
H
17NO
7
S (399.44): C, 48.11;
2
Method A: General Procedure: The protected nucleosides 8a-f
H, 4.29; N, 3.51. Found: C, 48.27; H, 4.55; N, 3.37.
(
(
1 mmol) were suspended in MeOH (15 ml), and concentrated HCl
0.5 ml) was added. The reaction mixture was heated for 2 h at 50 °C.
8.15. 5-((Z)-2-Thienylidene)-3-(β-D-ribofuranosyl)-2-thioxo-4-
To the resulting solution was added an ion exchange resin (Amberlite
thiazolidinone (10e)
−
IR-120, OH -form), previously washed with MeOH. After stirring for
5
min, the solution was filtered and evaporated in vacuo and the residue
Yield 284 mg (79%), yellow solid; mp 142–144 °C; IR (KBr): v
−
1
−1
−1
1
was purified by flash chromatography (eluent 0–5%, CHCl
3
/MeOH) to
3400 cm
(DMSO‑d
(OH), 1707 cm
(CO), 1224 cm
(CS); H NMR
afford the title compounds 10a-f.
6
): δ 3.46 (dd, J = 6.2, 12.1 Hz, 1H, 5′-H), 3.65 (dd, J = 4.8,
1
1.6 Hz, 1H, 5″-H), 3.78 (dd, J = 6.0, 6.2 Hz, 1H, 4′-H), 4.16 (dd,
8
.11. 5-((Z)-Benzylidene)-3-(β-D-ribofuranosyl)-2-thioxo-4-thiazolidinone
J = 5.8, 5.9 Hz, 1H, 3′-H), 4.73 (m, 2H, 2′-H, 3′-OH), 5.11 (d,
J = 6.1 Hz, 1H, 5′-OH), 5.32 (d, J = 5.3 Hz, 1H, 2′-OH), 6.30 (d,
J = 4.0 Hz, 1H, 1′-H), 7.34 (dd, J = 3.9, 5.0 Hz, 1H, 4″-H), 7.77 (d,
(
10a)
Yield 296 mg (84%); yellow solid; mp 170–172 °C; IR (KBr): v
J = 3.3 Hz, 1H, 3″-H), 8.10 (s, 1H, =CH), 8.15 (d, J = 5.0 Hz, 1H, 5″-
−
1
−1
−1
1
+
3
400 cm
(OH), 1717 cm
(CO), 1225 cm
(CS); H NMR
H); MS, m/z = 359 (M ); Anal. Calcd. for C13
H
13NO
5
S (359.44): C,
3
(
DMSO‑d
6
): δ 3.50 (dd, J = 6.3, 11.9 Hz, 1H, 5′-H), 3.65 (dd, J = 4.2,
43.44; H, 3.65; N, 3.90. Found: C, 43.53; H, 3.86; N, 3.64.
1
1.9 Hz, 1H, 5″-H), 3.80 (dd, J = 4.5, 4.6 Hz, 1H, 4′-H), 4.21 (dd,
J = 5.8, 5.8 Hz, 1H, 3′-H), 4.75 (m, 2H, 2′-H, 3′-OH), 5.15 (d,
J = 6.1 Hz, 1H, 5′-OH), 5.36 (d, J = 5.1 Hz, 1H, 2′-OH), 6.33 (d,
8.16. 5-((Z)-2-Furylidene)-3-(β-D-ribofuranosyl)-2-thioxo-4-thiazolidinone
(10f)
1
3
J = 3.6 Hz, 1H, 1′-H), 7.50–7.65 (m, 5H, Ar–H), 7.80 (s, 1H, =CH);
C
NMR (DMSO‑d
6
): δ 61.93 (C-5′), 70.30 (C-3′), 70.39 (C-2′), 85.03 (C-
Yield 260 mg (79%); yellow solid; mp 130–132 °C; IR (KBr): v
−
1
−1
−1
1
4
1
′), 90.17 (C-1′), 121.07 (=CH), 131.55 (C-5), 129.91, 130.97, 133.00,
3400 cm
(DMSO‑d
(OH), 1672 cm
(CO), 1230 cm
(CS); H NMR
+
33.74 (C–Ar), 166.49 (C-4), 195.18 (C-2); MS, m/z = 353 (M ); Anal.
6
): δ 3.42 (dd, J = 6.1, 11.9 Hz, 1H, 5′-H), 3.64 (dd, J = 4.9,
Calcd. for C15
H
15NO
5
S
2
(353.42): C, 50.98; H, 4.28; N, 3.96. Found: C,
11.7 Hz, 1H, 5″-H), 3.74 (dd, J = 6.0, 6.2 Hz, 1H, 4′-H), 4.16 (dd,
J = 5.8, 6.0 Hz, 1H, 3′-H), 4.70 (m, 2H, 2′-H, 3′-OH), 5.08 (d,
J = 6.0 Hz, 1H, 5′-OH), 5.28 (d, J = 5.3 Hz, 1H, 2′-OH), 6.32 (d,
J = 4.0 Hz, 1H, 1′-H), 6.80 (dd, J = 1.8, 2.8 Hz, 1H, 4″-H), 7.26 (d,
5
1.30; H, 4.62; N, 3.79.
8
.12. 5-((Z)-4-Methoxybenzylidene)-3-(β-D-ribofuranosyl)-2-thioxo-4-
thiazolidinone (10b)
J = 2.9 Hz, 1H, 3″-H), 7.60 (d, J = 1.8 Hz, 1H, 5″-H), 8.10 (s, 1H,
+
=
CH); MS, m/z = 343 (M ); Anal. Calcd. for C13
H
13NO
6
S (343.38):
2
8
.12.1. Yield 298 mg (78%); yellow solid; mp 178–180 °C; IR (KBr)
C, 45.47; H, 3.82; N, 4.08. Found: C, 45.63; H, 4.06; N, 3.89.
−
1
−1
−1
1
v 3378 cm
(OH), 1718 cm
(CO), 1228 cm
(CS); H NMR
Method B: To a mixture of the protected nucleoside 9 (265 mg,
1 mmol), anhydrous morpholine (0.09 g, 1 mmol) and anhydrous
ethanol (10 ml) was added benzaldehyde (0.11 g, 1 mmol). The mixture
was stirred until the starting material was consumed (12 h; TLC). The
reaction mixture was neutralized with HCl/MeOH. After stirring for
5 min, the solution was evaporated in vacuo and the residue was pur-
ified by flash chromatography (eluent 30–50%, diethyl ether/petro-
leum ether, 40–60 °C) to afford 230 mg (87%) of 10a as yellow solid.
(
DMSO‑d
6
): δ 3.46 (dd, J = 6.0, 12.2 Hz, 1H, 5′-H), 3.63 (dd, J = 5.3,
1
1.7 Hz, 1H, 5″-H), 3.80 (dd, J = 6.0, 6.3 Hz, 1H, 4′-H), 3.85 (s, 3H,
), 4.16 (dd, J = 6.0, 6.0 Hz, 1H, 3′-H), 4.72 (m, 2H, 2′-H, 3′-OH),
.12 (d, J = 6.2 Hz, 1H, 5′-OH), 5.34 (d, J = 5.3 Hz, 1H, 2′-OH), 6.33
d, J = 4.0 Hz, 1H, 1′-H), 7.15, 7.63 (2d, J = 8.8 Hz, 4H, Ar–H), 7.78
OCH
3
5
(
(
1
3
s, 1H, =CH); C NMR (DMSO‑d
6
): δ 55.87 (OCH ), 62.06 (C-5′),
3
7
1
1
0.35 (C-3′), 70.50 (C-2′), 85.19 (C-4′), 90.20 (C-1′), 115.46, 117.65,
25.69, 133.32, 133.84, 161.90 (=CH, C-5, C–Ar), 166.50 (C-4),
+
94.99 (C-2); MS, m/z = 383 (M ); Anal. Calcd. for C16
H
17NO
6
S
2
8.17. 5-((Z)-Arylidene)-3-(2′,3′,4′,6′-tetra-O-acetyl-β-D-mannopyranosyl)-
2-thioxo-4-thiazolidinones (13a-c)
(
383.44): C, 50.12; H, 4.47; N, 3.65. Found: C, 50.36; H, 4.71; N, 3.56.
8
.13. 5-((Z)-2,3-Dichlorobenzylidene)-3-(β-D-ribofuranosyl)-2-thioxo-4-
General Procedure: 5-((Z)-Arylidene)-2-thioxo-4-thiazolidinones
(6a,b,e) (5 mmol) was suspended in anhydrous MeCN (25 ml) at room
temperature. To this suspension was added NaH (50%, 0.26 g, 5 mmol),
and the mixture was stirred at room temperature for 30 min. The
mixture became clear after 15 min. 2,3,4,6-tetra-O-acetyl-α-D-manno-
pyranosyl bromide (12) (2.26 g, 5.5 mmol) was added, and the mixture
was stirred at room temperature for 12 h until the starting material was
consumed (TLC) and then filtered. The residue from the evaporation of
the filtrate under reduced pressure was purified by flash chromato-
graphy (eluent 30–50%, diethyl ether/petroleum ether, 40–60 °C) to
afford the title compounds 13a-c.
thiazolidinone (10c)
Yield 350 mg (83%); yellow solid; mp 137–139 °C; IR (KBr): v
−
1
−1
−1
1
3
400 cm
(OH), 1712 cm
(CO), 1230 cm
(CS); H NMR
(
DMSO‑d
6
+ D O): δ 3.46 (dd, J = 6.4, 11.9 Hz, 1H, 5′-H), 3.64 (dd,
2
J = 4.1, 11.9 Hz, 1H, 5″-H), 3.80 (dd, J = 6.1, 6.1 Hz, 1H, 4′-H), 4.16
(
dd, J = 5.8, 5.9 Hz, 1H, 3′-H), 4.69 (dd, J = 4.2, 5.6 Hz, 2′-H), 6.26 (d,
1
3
J = 4.0 Hz, 1H, 1′-H), 7.40–7.68 (m, 4H, Ar–H, =CH); C NMR
(
DMSO‑d
6
): δ 61.97 (C-5′), 70.38 (C-3′), 70.42 (C-2′), 85.24 (C-4′),
9
1
0.29 (C-1′), 125.33, 126.69, 128.79, 129.97, 130.33, 130.85, 135.97,
36.36 (=CH, C-5, C–Ar), 165.97 (C-4), 194.60 (C-2); MS, m/z = 422
+
(
M
); Anal. Calcd. for C15
H
13Cl
2
NO
5
S
2
(422.30): C, 42.66; H, 3.10; N,
8.18. 5-((Z)-Benzylidene)-3-(2′,3′,4′,6′-tetra-O-acetyl-β-D-mannopyranosyl)-
3
.32. Found: C, 42.75; H, 3.48; N, 3.12.
2-thioxo-4-thiazolidinones (13a)
−
1
8
.14. 5-((Z)-2-Hydroxy-3-methoxybenzylidene)-3-(β-D-ribofuranosyl)-2-
Yield 1.98 g (92%); yellow solid; mp 162–164 °C; IR: v 1752 cm
−1
−1
1
thioxo-4-thiazolidinone (10d)
(CO), 1747 cm
(CO), 1240 cm
(CS); H NMR (CDCl
3
): δ 1.95 (s,
3
H, Ac), 2.05 (s, 3H, Ac), 2.07 (s, 3H, Ac), 2.11 (s, 3H, Ac), 3.87–3.91
o
−1
Yield 350 mg (83%), yellow solid mp C; IR (KBr): v 3400 cm
(m, 1H, 5′-H), 4.23–4.26 (m, 2H, 6′-H, 6″-H), 5.53 (dd, J = 9.7, 9.8 Hz,
1H, 4′-H), 5.38 (dd, J = 9.1, 9.5 Hz, 2′-H), 6.16 (dd, J = 9.2, 9.2 Hz, 3′-
H), 6.35 (d, J = 9.4 Hz, 1H, 1′-H), 7.43–7.46 (m, 5H, Ar–H), 7.69 (s,
−
1
−1
1
(
OH), 1718 cm (CO) 1225 cm (CS); H NMR (DMSO‑d
6
+ D
2
O): δ
3
5
.44 (dd, J = 6.3, 11.9 Hz, 1H, 5′-H), 3.65 (dd, J = 4.2, 11.9 Hz, 1H,
″-H), 3.80 (dd, J = 6.0, 6.1 Hz, 1H, 4′-H), 3.87 (s, 3H, OMe), 4.18 (dd,
1H, =CH); 13C NMR (CDCl
): δ 20.38, 20.59, 20.62, 20.76 (4 Ac),
3
10

A.I. Khodair, et al.
Carbohydrate Research 487 (2020) 107894
6
1.67 (C-6′), 67.77 (C-2′), 67.81 (C-3′), 73.27 (C-4′), 74.89 (C-5′), 81.83
8.23. 5-((Z)-4-Methoxybenzylidene)-3-(β-D-mannopyranosyl)-2-thioxo-4-
(
(
(
C-1′), 120.52 (=CH), 130.94 (C-5), 129.35, 130.70, 133.11, 134.11
thiazolidinone (14b)
C–Ar), 165.86 (C-4), 169.40, 169.59, 170.10, 170.67 (4 Ac), 194.12
+
C-2); MS, m/z = 551 (M ); Anal. Calcd. for C24
H
25NO10
S
2
(551.59):
Yield: 351 mg (85%); yellow solid; mp 136–138 °C; IR (KBr): ν
−
1
−1
−1
1
C, 52.26; H, 4.57; N, 2.54. Found: C, 52.41; H, 4.80; N, 2.34.
3396 cm
DMSO‑d
H), 3.85 (s, 3H, OCH
H, 4′-OH), 5.22 (s, 1H, 3′-OH), 5.42 (s, 1H, 2′-OH), 5.86 (d,
J = 9.2 Hz, 1H, 1′-H), 7.11, 7.60 (2d, J = 8.6 Hz, 4H, Ar–H), 7.67 (s,
(OH), 1717 cm
(CO), 1226 cm
(CS); H NMR
(
6
): δ 3.13–3.46 (m, 4H, 6′-H, 6′-H, 5′-H, 4′-H), 3.70 (m, 1H, 3′-
3
), 4.42 (m, 1H, 2′-H), 4.62 (s, 1H, 6′-OH), 5.10 (s,
8
.19. 5-((Z)-4-Methoxybenzylidene)-3-(2′,3′,4′,6′-tetra-O-acetyl-β-D-
1
mannopyranosyl)-2-thioxo-4-thiazolidinone (13b)
1
3
1
H, =CH); C NMR (DMSO‑d
6
): δ 55.62 (OCH ), 61.15 (C-6′), 67.68
3
−
1
Yield 1.97 g (68%); yellow solid; mp 216–218 °C; IR: ν 1750 cm
(
(
(
C-2′), 69.94 (C-3′), 77.60 (C-4′), 80.78 (C-5′), 84.98 (C-1′), 117.63
−
1
−1
1
(
CO), 1746 cm
(CO), 1238 cm
(CS); H NMR (CDCl
3
): δ 1.94 (s,
=CH), 120.81 (C-5), 115.17, 125.57, 132.89, 161.60 (C–Ar), 166.16
3
H, Ac), 2.04 (s, 3H, Ac), 2.07 (s, 3H, Ac), 2.10 (s, 3H, Ac), 3.86–4.28
+
C-4), 195.26 (C-2); MS, m/z
=
413 (M ); Anal. Calcd. for
(
m, 6H, OCH
3
, 5′-H, 6′-H, 6″-H), 5.30 (dd, J = 9.7, 9.8 Hz, 1H, 4′-H),
.38 (dd, J = 9.1, 9.5 Hz, 2′-H), 6.16 (dd, J = 9.2, 9.2 Hz, 3′-H), 6.35
C
17
H
19NO
7
S (413.47): C, 49.38; H, 4.63; N, 3.39. Found: C, 49.53; H,
2
5
4
.80; N, 3.14.
(
(
d, J = 9.4 Hz, 1H, 1′-H), 7.00, 7.46 (2d, J = 8.5 Hz, 4H, Ar–H), 7.68
1
3
s, 1H, =CH); C NMR (CDCl
3
): δ 20.42, 20.61, 20.64, 20.78 (4 Ac),
9
. Computational details
5
5
5.56 (OCH
3
), 61.71 (C-6′), 67.82 (C-2′, C-3′), 73.36 (C-4′), 74.88 (C-
′), 81.84 (C-1′), 114.96, 117.38, 125.87, 132.89, 134.22, 161.89
The molecular structures of the investigated compounds were op-
(
C–Ar, =CH, C-5), 166.06 (C-4), 169.42, 169.57, 170.14, 170.70 (4
timized using DFT (density functional theory) in combination with the
Beck's three parameter exchange functional along with the Lee-Yang-
Parr non local correlation functional (B3LYP) [54–56] with 6-
+
Ac), 194.17 (C-2); MS, m/z = 581 (M ); Anal. Calcd. for C25
H
27NO11
S
2
(
581.61): C, 51.63; H, 4.68; N, 2.41. Found: C, 51.85; H, 4.78; N, 2.32.
3
1 + G(d) basis set which is implemented in Gaussian 09 program
8
.20. 5-((Z)-2-Thienylidene)-3-(2′,3′,4′,6′-tetra-O-acetyl-β-D-
package [57]. An estimate of molecular properties related to molecular
reactivity was calculated with DFT/B3LYP combination [58]. The mo-
lecular properties include the highest occupied molecular orbital
(HOMO), the lowest unoccupied molecular orbital (LUMO), global
hardness and softness, electronegativity, electron affinity, ionization
potential, etc [31,59–61].
mannopyranosyl)-2-thioxo-4-thiazoli-dinone (13c)
−
1
Yield: 2.00 g (72%); yellow solid; mp 148–150 °C; IR: v 1750 cm
−
1
−1
1
(
CO), 1748 cm
(CO), 1236 cm
(CS); H NMR (CDCl
3
): δ 1.94 (s,
3
5
5
H, Ac), 2.04 (s, 3H, Ac), 2.07 (s, 3H, Ac), 2.10 (s, 3H, Ac), 3.88 (m, 1H,
′-H), 4.27 (m, 6H, 6′-H, 6″-H), 5.30 (dd, J = 9.7, 9.8 Hz, 1H, 4′-H.),
.38 (dd, J = 9.1, 9.6 Hz, 2′-H), 6.14 (dd, J = 9.1, 9.3 Hz, 3′-H), 6.32
10. Shape alignment and ROCS [51–53]
(
d, J = 9.3 Hz, 1H, 1′-H), 7.20 (dd, J = 0.3.8, 5.0 Hz, 1H, 4″-H), 7.42
d, J = 3.7 Hz, 1H, 3″-H), 7.72 (d, J = 5.0 Hz, 1H, 5″-H), 7.89 (s, 1H,
(
Basic method to represent shape and color features in ROCS is using
ROCs application Open Eye scientific software. BTR1 and GSK were
selected as query molecules. Compounds library was adopted as the
database file. Both query and database files were energy minimized by
Omega applications. ROCS runs were employed by personal PC in very
fast using vROCS interface. vROCS was employed to run and analyze/
visualize the results. ROCS application searched the database with the
query to find molecules with similar shape and colors. Compounds
conformers were scored based upon the Gaussian overlap to the query
and the best scoring parameters is Tanimoto Combo scores
1
3
=
CH); C NMR (CDCl ): δ 20.40, 20.60, 20.63, 20.77 (4 Ac), 61.69 (C-
3
6
′), 67.80 (C-2′, C-3′), 73.31 (C-4′), 74.89 (C-5′), 81.93 (C-1′), 118.50
(
(
=CH), 126.39 (C-5), 129.00, 133.21, 134.33, 137.83 (C–Ar), 165.66
C-4), 169.42, 169.58, 170.13, 170.70 (4 Ac), 193.35 (C-2); MS, m/
+
z = 557 (M ); Anal. Calcd. for C22
H
23NO10
3
S (557.62): C, 47.39; H,
4
.16; N, 2.51. Found: C, 47.62; H, 4.38; N, 2.30.
8
.21. 5-((Z)-Arylidene)-3-(β-D-mannopyranosyl)-2-thioxo-4-thiazolidinones
(
14a,b)
(
shape + color), the highest score is the best matched with query
compound.
General Procedure: The protected nucleosides 13a,b (1 mmol) were
suspended in MeOH (15 ml), and concentrated HCl (0.5 ml) was added.
The reaction mixture was heated for 2 h at 50 °C. To the resulting so-
Declaration of competing interest
There is no conflict of interest between the Authors.
Acknowledgements
−
lution was added an ion exchange resin (Amberlite IR-120, OH -form),
previously washed with MeOH. After stirring for 5 min, the solution
was filtered and evaporated in vacuo and the residue was purified by
flash chromatography (eluent 0–5%, CHCl /MeOH) to afford the title
3
compounds 14a,b.
We thank ADIR (Groupe Servier, paris) for carrying out the antitumor
testing of the prepared new deprotected nucleosides. Ahmed I. Khodair
is grateful for an Alexander von Humboldt-Fellowship.
8
.22. 5-((Z)-Benzylidene)-3-β-D-mannopyranosyl-2-thioxo-4-
thiazolidinone (14a)
Appendix A. Supplementary data
Yield: 306 mg (80%); yellow solid; mp 148–150 °C; IR (KBr): v
−
1
−1
−1
1
3
392 cm (OH), 1718 cm (CO), 1225 cm (CS); H NMR (CD
3
OD-
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.carres.2019.107894.
d
4
): δ 3.22 (m, 1H, 4′-H), 3.34 (m, 3H, 5′-H, 6′-H, 6″-H), 3.60 (m, 1H, 3′-
H), 3.82 (m, 1H, 2′-H), 6.00 (d, J = 9.4 Hz, 1H, 1′-H), 7.32–7.48 (m,
1
3
5
6
1
1
H, Ar–H), 7.60 (s, 1H, =CH); C NMR (CD
3
OD-d
6
): δ 62.74 (C-6′),
References
9.43 (C-2′), 71.30 (C-3′), 79.16 (C-4′), 81.50 (C-5′), 86.02 (C-1′),
22.53 (=CH), 127.24 (C-5), 130.47, 131.70, 131.81, 131.92, 133.81,
[1] T. Tomasic, L.P. Masic, Rhodanine as a privileged scaffold in drug discovery, Curr.
Med. Chem. 16 (2009) 1596–1629, https://doi.org/10.2174/
+
34.65 (C–Ar), 168.15 (C-4), 196.85 (C-2); MS, m/z = 383 (M ); Anal.
0
92986709788186200.
Calcd. for C16
H17NO
6
S (383.44): C, 50.12; H, 4.47; N, 3.65. Found: C,
2
[
2] T. Tomasic, L.P. Masic, Rhodanine as a scaffold in drug discovery: a critical review
5
0.36; H, 4.67; N, 3.45.
11

A.I. Khodair, et al.
Carbohydrate Research 487 (2020) 107894
of its biological activities and mechanisms of target modulation, Expert Opin. Drug
[24] A.I. Khodair, H.I. EL-Subagh, A.A. El-Emam, Synthesis of certain 5-substituted 2-
thiohydantoin derivatives as potential cytotoxic and antiviral agents, Boll. Chim.
Farm. 136 (1997) 561–567 [PMID: 9440349].
Discov. 7 (2012) 549–560, https://doi.org/10.1517/17460441.2012.688743.
3] P. Hirsova, J. Dolezel, M. Kucerova-Chlupacova, J. Kunes, V. Pilarova, L. Novakova,
v. Opletalova, (Z)-3-amino-5-(pyridin-2-ylmethylidene)-2-thioxo-1,3thiazolidin-4-
one, Molbank 4 (2015) M872, https://doi.org/10.3390/M872.
[
[
[25] A.M. Al-Obaid, H.I. EL-Subagh, A.I. Khodair, M.M.A. Elmazar, 5-substituted-2-
thiohydantoin analogs as a novel class of antitumor agents, Anti Canccer Drugs 7
(1996) 873–880, https://doi.org/10.1097/00001813-199611000-00009.
[26] A.I. Khodair, Glycosylation of 2-thiohydantoin derivatives, synthesis of some novel
s-alkylated and s-glucosylated hydantoins, Carbohydr. Res. 331 (2001) 445–453,
https://doi.org/10.1016/S0008-6215(01)00040-4.
4] J. Dolezel, V. Opletalova, M. Vejsova, P. Hirsova, Evaluation of thiazolidine deri-
vatives, abstracts of the 5th international postgraduate research symposium on
pharmaceutics (IPORSIP2007), istanbul, Turkey, 13–15 september 2007, Acta
Pharm. Sci. 49 (2007) 31–43 ([Google scholar]).
[
5] P. Petrik, J. Kunes, M. Vejsova, J. Jampilek, E. Spaningerova, D. Kesetovicova,
M. Vlckova, M. Majd, S. Kalafutova, V. Opletalova, Antifungal and anti-
[27] A.I. Khodair, Synthesis of 2-thiohydantoins and their S-glucosylated derivatives as
potential antiviral and antitumor agents, Nucleosides Nucleotides Nucleic Acids 20
(2001) 1735–1750, https://doi.org/10.1081/NCN-100105908.
mycobacterial properties of 5-arylmethylidenerhodanines and their N
3
-substituted
th
analogues, abstracts of the 5 international postgraduate research symposium on
pharmaceutics (IPORSIP-2007), istanbul, Turkey, 13–15 september 2007, Acta
Pharm. Sci. 49 (2007) 77–87 ([Google scholar]).
[28] K.N. Houk, F. Liu Holy, Holy grails for computational organic chemistry and bio-
chemistry, Acc. Chem. Res. 50 (2017) 539–543, https://doi.org/10.1021/acs.
accounts.6b00532.
[
6] J. Dolezel, P. Hirsova, V. Opletalova, J. Dohnal, M. Vejsova, J. Kunes, J. Jampilek,
Rhodanineacetic acid derivatives as potential drugs: preparation, hydrophobic
properties and antifungal activity of (5-arylalkylidene-4-oxo-2-thioxo-1,3-thiazo-
lidin-3-yl)acetic acids, Molecules 14 (2009) 4197–4212, https://doi.org/10.3390/
molecules14104197.
[29] M.M. Kabanda, L.C. Murulana, M. Ozcan, F. Karadag, Quantum chemical studies on
the corrosion inhibition of mild steel by some triazoles and benzimidazole deriva-
tives in acidic medium, Int. J. Electrochem. Sci. 7 (2012) 5035–5056 ([Google
Scholar]).
[30] P. Udhayakala, A. Jayanthi, T.V. Rajendiran, Adsorption and quantum chemical
studies on the inhibition potentials of some formazan derivatives, Der Pharma
Chem. 3 (2011) 528–539 ([Google Scholar]).
[
[
7] V. Opletalova, J. Dolezel, V. Buchta, M. Vejsova, P. Paterova, Antifungal effects of
(
5Z)-5-arylmethylidenerhodanines with a special view to members of mucorales,
Folia Pharm. Univ. Carol. 42 (7–13) (2014) ([Google scholar]).
8] V. Opletalova, J. Dolezel, K. Kralova, M. Pesko, J. Kunes, J. Jampilek, Synthesis and
characterization of (Z)-5-arylmethylidenerhodanines with photosynthesis-in-
hibiting properties, Molecules 16 (2011) 5207–5227, https://doi.org/10.3390/
molecules16065207.
[31] M.K. Awad, M.S. Masoud, M.A. Shaker, A.E. Ali, MP2 and DFT theoretical studies of
the geometry, vibrational and electronic absorption spectra of 2-aminopyrimidine,
Res. Chem. Intermed. 39 (2013) 2741–2761, https://doi.org/10.1007/s11164-012-
0795-3.
[32] F.M. Atlam, M.K. Awad, E.A. El-bastawissy, Computational simulation of the effect
of quantum chemical parameters on the molecular docking of HMG-CoA reductase
drugs, J. Mol. Struct. 1075 (2014) 311–326, https://doi.org/10.1016/j.molstruc.
2014.06.045.
[
9] Y. Ohishi, T. Mukai, M. Nagahara, M. Yajima, N. Kajikawa, K. Miyahara, T. Takano,
Preparations of 5-alkylmethylidene-3-carboxymethylrhodanine derivatives and
their aldose reductase inhibitory activity, Chem. Pharm. Bull. 38 (1990)
1
911–1919, https://doi.org/10.1248/cpb.38.1911.
[33] A.I. Khodair, A.M. Attia, E.A. Gendy, Y.A.M.M. Elshaier, M.A. El-Magd, Design,
synthesis and cytotoxicity evaluation of some novel of S-glycoside of 2-thioxopyr-
idine and N-glycoside of 2-oxopyridine derivatives as antibreast cancer, J.
Heterocycl. Chem. 56 (2019) 1733–1747, https://doi.org/10.1002/jhet.3527.
[34] A.M. Attia, A.I. Khodair, E.A. Gendy, M.A. El-Magd, Y.A.M.M. Elshaier, New 2-
oxopyridine/2-thiopyridine derivatives tethered to a benzotriazole with cytotoxi-
city on MCF7 cell lines and with antiviral activities, Lett. Drug Des. Discov. 16
(2019) 1–14, https://doi.org/10.2174/1570180816666190220123547.
[35] L.M. Werbel, N. Headen, E.F. Elslager, 3-phenylrhodanines as potential antimalarial
agents, J. Med. Chem. 11 (1968) 364–365, https://doi.org/10.1021/jm00308a040.
[36] F.C. Brown, C.K. Bradsher, S.M. Bond, R.J. Granthan, Mildew-preventing activity of
rhodanine derivatives, Ind. Eng. Chem. 46 (1954) 1508–1512, https://doi.org/10.
1021/ie50535a054.
[
[
10] Y. Momose, K. Meguro, H. Ikeda, C. Hatanaka, S. Oi, T. Sohda, Studies on anti-
diabetic agents X: synthesis and biological activities of pioglitazone and related
compounds, Chem. Pharm. Bull. 39 (1991) 1440–1445, https://doi.org/10.1248/
cpb.39.1440.
11] K. Sudo, Y. Matsumoto, M. Matsushima, M. Fujiwara, K. Konno, K. Shimotohno,
S. Shigeta, T. Yokota, novel hepatitis C virus protease inhibitors: thiazolidine de-
rivative, Biochem. Biophys. Res. Commun. 238 (1997) 643–647, https://doi.org/
1
0.1006/bbrc.1997.7358.
[
[
12] M.M. Sim, S.B. Ng, A.D. Buss, S.C. Crasta, K.L. Goh, S.K. Lee, Rhodanines as novel
inhibitors of UDP-N-acetylmuramate/L-alanine ligase, Bioorg. Med. Chem. Lett 12
(
2002) 697–699, https://doi.org/10.1016/S0960-894X(01)00832-0.
13] R. Frlan, A. Kovac, D. Blanot, S. Gobec, S. Pecar, A. Obreza, Design and synthesis of
novel N-benzylidenesulfonohydrazide inhibitors of MurC and MurD as potential
antibacterial agents, Molecules 13 (2008) 11–30, https://doi.org/10.3390/
molecules13010011.
[37] H. Vorbruggen, K. Krolikiewicz, B. Bennua, Nucleoside syntheses XXII: nucleoside
synthesis with trimethylsilyl triflate and perchlorate as catalysts, Chem. Ber. 114
(1981) 1234–1255, https://doi.org/10.1002/cber.19811140404.
[
[
14] K. Kristan, M. Kotnik, M. Oblak, U.J. Urleb, New high-throughput fluorimetric assay
for discovering inhibitors of UDP-N-acetylmuramyl-L-alanine: D-glutamate (MurD)
ligase, Biomol. Screen. 14 (2009) 412–418, https://doi.org/10.1177/
[38] A.I. Khodair, Convenient synthesis of 2-arylidene-5H-thiazolo[2,3-b]quinazoline-
3,5[2H]-diones and their benzoquinazoline derivatives, J. Heterocycl. Chem. 39
(2002) 1153–1160, https://doi.org/10.1002/jhet.5570390607.
1
087057109332597.
[39] U. Piantini, O.W. Sorensen, R.R. Ernst, Multiple quantum filters for elucidating
NMR coupling networks, J. Am. Chem. Soc. 104 (1982) 6800–6801, https://doi.
org/10.1021/ja00388a062.
15] B. Bulic, M. Pickhardt, I. Khilstunova, J. Biernat, E.M. Mandelkow, E. Mandelkow,
H. Waldmann, Rhodanine-based tau aggregation inhibitors in cell models of tauo-
pathy, Angew. Chem. Int. Ed. 46 (2007) 9215–9219, https://doi.org/10.1002/anie.
[40] A.A. Bothner-By, R.L. Stephensen, J. Lee, C.D. Warren, R.W. Jeanloz, Structure
determination of tetrasaccharide: transient nuclear overhauser effects in the ro-
tating frame, J. Am. Chem. Soc. 106 (1984) 811–813, https://doi.org/10.1021/
ja00315a069.
2
00704051.
[
[
16] E. Zeiger, B. Anderson, S. Haworth, T. Lawlor, W. Mortelmans, Salmonella muta-
genicity tests: III. Results from the testing of 255 chemicals, Environ. Mutagen. 9
(
1987) 1–109, https://doi.org/10.1002/em.2860090602.
[41] A. Bax, D.G. Davis, Practical aspects of two-dimensional transverse NOE spectro-
scopy, J. Magn. Reson. 63 (1985) 207–213 ([Google Scholar]).
17] N. Hotta, Long-term clinical effects of epalrestat, an aldose reductase inhibitor, on
diabetic peripheral neuropathy: the 3-year, multicenter, comparative aldose re-
ductase inhibitor-diabetes complications trial, Diabetes Care 29 (2006) 1538–1544,
https://doi.org/10.2337/dc05-2370.
[42] C. Griesinger, R.R. Ernst, Frequency offset effects and their elimination in NMR
rotating-frame cross-relaxation spectroscopy, J. Magn. Reson. 75 (1987) 261–271,
https://doi.org/10.1016/0022-2364(87)90035-7.
[
[
18] B.T. Moorthy, S. Ravi, M. Srivastava, K. K, S.C. Chiruvella, Novel rhodanine deri-
vatives induce growth inhibition followed by apoptosis, Med. Chem. Lett. 20 (2010)
[43] G. Gosselin, H.F. Loukil, A. Mathieu, A. Mesli, J.L. Imbach, Ribosylation of various
2-mercaptobenzoazole, J. Heterocycl. Chem. 15 (1978) 657–664, https://doi.org/
10.1002/jhet.5570150427.
6
297–6301, https://doi.org/10.1016/j.bmcl.2010.08.084.
1
13
19] M. Azizmohammadi, M. Khoobi, A. Ramazani, S. Emami, 2H-chromene derivatives
bearing thiazolidine-2,4-dione, rhodanine or hydantoin moieties as potential an-
ticancer agents, Eur. J. Med. Chem. 59 (2013) 15–22, https://doi.org/10.1016/j.
ejmech.2012.10.044.
[44] N.A. Al-Masoudi, Y.A. Al-Soud, A. Geyer, H- and C-NMR study of some 6,7- di-
haloquinolone nucleosides and their derivatives, Spectrosc. Lett. 31 (1998)
1031–1038, https://doi.org/10.1080/00387019808003281.
[45] D. Villemin, A.B. Alloun, Synthesis of α-thioacrylic acids and phosphonothiono-
thiazolidinones, phosphorus, sulfur, silicon and reat, Elmen 79 (1993) 33–41,
https://doi.org/10.1080/10426509308034395.
[
20] S.P. Mandal, A. Garg, S.S. Sahetya, S.R. Nagendra, H.S. Sripad, M.M. Manjunath,
Sitaram, M. Soni, R.N. Baig, S.V. Kumarc, B.R.P. Kumar, Novel rhodanines with
anticancer activity: design, synthesis and CoMSIA study, RSC Adv. 6 (2016)
[46] A.A. El-Barbary, A.I. Khodair, E.B. Pedersen, C. Nielsen, Synthesis of uridine with 5-
methylene-2-thiohydantoin substituent in the 5-position, Liebigs Ann. Chem.
(1994) 619–621, https://doi.org/10.1002/jlac.199419940613.
5
8641–58653, https://doi.org/10.1039/c6ra08785j.
[
[
21] R. Kumar, J.W. Lown, Synthesis and antitumor cytotoxicity evaluation of novel
thiazole-containing glycosylated polyamides, Eur. J. Org. Chem. 24 (2003)
[47] T. Ishida, Y. In, M. Inoue, Y. Ueno, C. Tanaka, Structural elucidation of epalrestat
(ONO-2235), a potent aldose reductase inhibitor, and isomerization of its double
bonds, Tetrahedron Lett. 30 (1989) 959–962, https://doi.org/10.1016/S0040-
4039(00)95290-0.
4
842–4851, https://doi.org/10.1002/ejoc.200300532.
22] S.D. Knight, N.D. Adams, J.L. Burgess, A.M. Chaudhari, M.G. Darcy, C.A. Donatelli,
J.I. Luengo, K.A. Newlander, C.A. Parrish, L.H. Ridgers, M.A. Sarpong, S.J. Schmidt,
G.S. Van Aller, J.D. Carson, M. Diamond, A.P.A. Elkins, C.M. Gardiner, E. Garver,
S.A. Gilbert, R.R. Gontarek, J.R. Jackson, K.L. Kershner, L. Luo, K. Raha, C.S. Sherk,
C.M. Sung, D. Sutton, P.J. Tummino, K.R.W. grzyn, R. J Auger, D. Dhanak,
Discovery of GSK2126458, a highly potent inhibitor of PI3K and the mammalian
target of rapamycin, ACS Med. Chem. Lett. 1 (2010) 39–43, https://doi.org/10.
[48] R.U. Lemieu, Reactions of carbohydrates, Methods Carbohydr. Chem. 2 (1963)
221–222 ([Google Scholar]).
[49] A.I. Khodair, J.P. Gesson, A new approach for the N-galactosylation and S-ga-
lactosylation of 5-arylidene-2-thioxo-4-thiazolidinones, Carbohydr. Res. 364 (2011)
2831–2837, https://doi.org/10.1016/j.carres.2011.09.035.
1
021/ml900028r.
[50] A. Monks, D. Scudiero, P. Skehan, R. Shoemaker, K. Poull, D. Vistica, C. Hose,
J. Langly, P. Cronise, A. Viagro-Wolff, M. Gray-Goodrish, H. Compell, M.J. Boyd,
Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured
human tumor cell lines, J. Natl. Cancer Inst. 83 (1991) 757–766, https://doi.org/
[
23] A.A. El-Barbary, A.I. Khodair, E.B. Pedersen, C. Nielsen, S-glucosylated hydantoins
as new antiviral agents, J. Med. Chem. 37 (1994) 73–77, https://doi.org/10.1021/
jm00027a009.
12

A.I. Khodair, et al.
Carbohydrate Research 487 (2020) 107894
1
0.1093/jnci/83.11.757.
https://doi.org/10.1103/PhysRevB.37.785.
[
[
51] ROCS, version 2.5.1.4; OpenEye http://www.openey.com.
52] VIDA, version 4.1.2, OpenEye Scientific software, santa Fe, NM (USA), http://www.
eyesopen.com.
[57] M.J. Frisch, Gaussian 09, Revision B.01, Gaussian, Inc., Pittsburgh, (2009) https://
gaussian.com/g09citation/.
[58] P. Senet, Letters, chemical harnesses of atoms and molecules from frontier orbitals,
Chem. Phys. Lett. 275 (1997) 527–532, https://doi.org/10.1016/S0009-2614(97)
00799-9.
[
53] K.R.A. Abdellatif, W.A.A. Fadaly, G.M. Kamel, Y.A.M.M. Elshaier, M.A. El-Magd,
design, synthesis, modeling studies and biological evaluation of thiazolidine deri-
vatives containing pyrazole core as potential anti-diabetic PPAR-γ agonists and anti-
inflammatory COX-2 selective inhibitors, Bioorg. Chem. 82 (2019) 86–99, https://
doi.org/10.1016/j.bioorg.2018.09.034.
[59] W. Langenaeker, P. Geerlings, F. De Proft, Theory, conceptual density functional,
Chem. Rev. 103 (2003) 1793–1874, https://doi.org/10.1021/cr990029p.
[60] S.L. PU, Materials for nonlinear optics-chemical perspectives, chapter 22: observing
high second harmonic generation and control of molecular alignment in one di-
mension, ACS Symp. Ser. 455 (1991) 331–342 ([Google Scholar]).
[61] E. Scrocco, J. Tomasi, Electronic molecular structure, reactivity and intermolecular
forces: an euristic interpretation by means of electrostatic molecular potentials,
Adv. Quant. Chem. 11 (1978) 115–193, https://doi.org/10.1016/S0065-3276(08)
60236-1.
[
54] A.D. Becke, Density-functional thermochemistry II: the effect of the Perdew-Wang
generalized-gradient correlation correction, J. Chem. Phys. 97 (1992) 9173–9177,
https://doi.org/10.1063/1.463343.
[
[
55] A.D. Becke, A new mixing of Hartree–Fock and local density-functional theories, J.
Chem. Phys. 98 (1993) 1372–1377, https://doi.org/10.1063/1.464304.
56] C. Lee, W. Yang, R.G. Parr, Development of the colle-salvetti correlation-energy
formula into a functional of the electron density, Phys. Rev. B. 37 (1988) 785–789,
13