Synthesis, molecular modeling and anti-cancer evaluation of a series of quinazoline derivatives

Article abstract of DOI:10.1016/j.carres.2019.107832

Quinazolines were surveyed as biologically relevant moieties against different cancer cell lines, so in the present study, we analyzed novel derivatives as target-oriented chemotherapeutic anti-cancer drugs. A series of 3-substituted 2-thioxo-2,3-dihydro-1H-quinazolin-4-ones 4a-e were synthesized via the reaction of 2-aminobenzoic acid (1) with isothiocyanate derivatives 2a-e. S-alkylation and S-glycosylation were carried via the reaction of 4a-e with alkyl halides and α-glycopyranosyl bromides 7a,b under anhydrous alkaline and glycoside conditions, respectively. The S-alkylated and S-glycosylated structures, and not that of the N-alkylated and N-glycosylated isomers, have been selected for the products. Conformational analysis has been studied by homo- and heteronuclear two-dimensional NMR methods (DQF-COSY, HMQC, and HMBC). The S site of alkylation and glycosylation were determined from the ¹H, ¹³C heteronuclear multiple-quantum coherence (HMQC) experiments. All derivatives were subjected to molecular docking calculations, which selected some derivatives (5n, 8c, 8g, 9c, and 9a) as promising ones based on their excellent binding affinities towards the EGFR tyrosine kinase molecular target. The in vitro cytotoxic activity against MCF-7 and HepG2 cell lines showed effective anti-proliferative activity of the analyzed derivatives with lower IC₅₀ values especially 9a with IC₅₀ = 2.09 and 2.08 μM against MCF-7 and HepG2, respectively, and their treatments were safe against the normal cell line Gingival mesenchymal stem cells (GMSC). Moreover, RT-PCR reaction investigated the apoptotic pathway for the compound 9a, which activated the P53 genes and its related genes. So, further work is recommended for developing it as a chemotherapeutic drug.

Full text of DOI:10.1016/j.carres.2019.107832

CarbohydrateResearch486(2019)107832
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Synthesis, molecular modeling and anti-cancer evaluation of a series of
quinazoline derivatives
Ahmed I. Khodaira,∗, Mona A. Alsafib, Mohamed S. Nafiec
a Chemistry Department, Faculty of Science, Kafrelsheikh University, 33516, Kafrelsheikh, Egypt
b Chemistry Department, College of Science, Taibah University, 1343, Al-Madinah Al-Monawarah, Saudi Arabia
c 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
Keywords:
Quinazolines were surveyed as biologically relevant moieties against different cancer cell lines, so in the present
study, we analyzed novel derivatives as target-oriented chemotherapeutic anti-cancer drugs. A series of 3-sub-
stituted 2-thioxo-2,3-dihydro-1H-quinazolin-4-ones 4a-e were synthesized via the reaction of 2-aminobenzoic
acid (1) with isothiocyanate derivatives 2a-e. S-alkylation and S-glycosylation were carried via the reaction of
4a-e with alkyl halides and α-glycopyranosyl bromides 7a,b under anhydrous alkaline and glycoside conditions,
respectively. The S-alkylated and S-glycosylated structures, and not that of the N-alkylated and N-glycosylated
isomers, have been selected for the products. Conformational analysis has been studied by homo- and hetero-
nuclear two-dimensional NMR methods (DQF-COSY, HMQC, and HMBC). The S site of alkylation and glyco-
sylation were determined from the 1H, 13C heteronuclear multiple-quantum coherence (HMQC) experiments. All
derivatives were subjected to molecular docking calculations, which selected some derivatives (5n, 8c, 8g, 9c,
and 9a) as promising ones based on their excellent binding affinities towards the EGFR tyrosine kinase molecular
target. The in vitro cytotoxic activity against MCF-7 and HepG2 cell lines showed effective anti-proliferative
activity of the analyzed derivatives with lower IC50 values especially 9a with IC50 = 2.09 and 2.08 μM against
MCF-7 and HepG2, respectively, and their treatments were safe against the normal cell line Gingival me-
senchymal stem cells (GMSC). Moreover, RT-PCR reaction investigated the apoptotic pathway for the compound
9a, which activated the P53 genes and its related genes. So, further work is recommended for developing it as a
chemotherapeutic drug.
2-aminobenzoic acid
3-Substituted 2-thioxo-2,3-dihydro-1H-
quinazolin-4-ones
Quinazolinone S-nucleosides
Molecular docking
MTT assay
apoptosis
1. Introduction
mate antitumor chemotherapeutic agent [14–18]. It was reported
that 2-thioxo-3-substituted quinazolinones (I) [19] and their S-me-
Quinazolines are considered to be an important chemical scaffold
of various physiological significance and pharmaceutical utility.
thyl thioether counterparts (II), in addition to the 6-substituted
quinazolinone derivatives (III) showed promising antitumor po-
tency [20]. As the first part of this study, we at this moment report
the synthesis and spectroscopy of a new series of S-alkylated bearing
3-substituted-2-thioxo-2,3-dihydro-1H-quinazolin-4-ones bases as
potential antiviral and antitumor activities (Scheme 1).
They possess
a variety of biological effects including anti-
hypertensive [1,2], antimicrobial [3,4], antihyperlipidemic [5,6],
anti-inflammatory [7,8] and anticonvulsant [9–13] activities.
Moreover, many quinazolines contributed to the quest for an ulti-
∗ Corresponding author.
E-mail address: khodair2020@yahoo.com (A.I. Khodair).
https://doi.org/10.1016/j.carres.2019.107832
Received 6 July 2019; Received in revised form 2 October 2019; Accepted 3 October 2019
Availableonline07October2019
0008-6215/©2019ElsevierLtd.Allrightsreserved.

A.I. Khodair, et al.
CarbohydrateResearch486(2019)107832
Moreover, nucleoside analogs constitute an important class of
therapeutic agents in the treatment of cancers and viral infections
[21,22]. 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 [23–26].
Glycosides of structurally similar heterocyclic systems have been re-
ported before [27–30]. In continuation of our work on the synthesis of
novel nucleosides as potential antiviral, antitumor agents and keeping
in mind the biological significance of 2-thioxo-quinazolin-4-ones
[31–37]. As the second part of this study, we at this moment report the
synthesis and spectroscopy of a new series of S-glycosylated bearing 3-
substituded-2-thioxo-2,3-dihydro-1H-benzo [g]-quinazolin-4-onebases
as potential antiviral and antitumor activities (Scheme 2). This is the
first time to prepare S-glycosides of 3-substituted-2-thioxo-2,3-dihydro-
1H-quinazolin-4-ones via new synthetic strategies. The previous studies
of Abdel-Megeed et al. [38] and El-Barbary et al. [39] succeeded to
prepare S-glycosides of 3-substituted 2-thioxoquinazolin-4-one deriva-
tives, and they did not succeed to get the corresponding deprotected S-
glycosides of 3- substituted 2-thioxoquinazolin-4-one derivatives.
absolute ethanol in the presence of triethylamine as a base catalyst.
Compounds 4a–e were then reacted with the appropriate alkyl halides
namely ethyl bromide, ethyl bromoacetate and finally 1-chloro-2-
methoxyethaneto yield the corresponding 3-substituted2-alkylsulfanyl-
2,3-dihydro-1H-quinazolin-4-ones 5a-e, 3-substituted4-oxo-3,4-dihy-
droquinazolin-2-ylsulfanyl-acetic acid ethyl esters 5f-j, 3-substituted2-
ethoxy-methyl-sulfanyl-2,3-dihydro-1H-quinazolin-4-ones 5k-o, re-
spectively (Scheme 1). The structures of 4a-e and 5a-o were established
and confirmed by elemental analyses and spectral data (IR, 1H NMR,
13C NMR, and MS). The IR absorption spectra of 4a–e were char-
acterized the presence of a signal for NH group at vmax 3176-3247 cm−1
and the presence of a signal for the thiocarbonyl group at vmax1262-
1300 cm−1. While the IR absorption spectra of 5a–o were characterized
by the absence of signals for NH and C]S groups. 1H NMR (500 MHz,
DMSO‑d6) spectrum of compound 4b showed a triplet at δH1.23 ppm
(J = 6.50 Hz) assigned to the methyl proton, a quartet at 4.46 ppm
(J = 7.0 Hz) assigned to the methylene proton, a triplet at δH 7.33 ppm
(J = 7.50 Hz) assigned to 6-H, a doublet at δH 7.39 ppm (J = 8.50 Hz)
assigned to 8-H, a singlet at δH 7.74 ppm assigned to 7-H, a doublet at
δH7.90 ppm (J = 7.50 Hz) assigned to 5-H and a singlet at δH 13.00 ppm
assigned to NH. This agrees with the 1H NMR (300 MHz, DMSO‑d6)
spectrum of 3-(4-methoxyphenyl)-2-thioxo-2,3-dihydroquinazolin-
4(1H)-one [40], whose NH appears at δH 13.02 ppm. The 13C NMR
(500 MHz, DMSO‑d6) spectrum of 4d showed a singlet at δC160.27 ppm
and 176.58 ppm assigned to the carbonyl group at C-4 and the thio-
carbonyl group at C-2, respectively. These data are also in agreement
with the 13C NMR (300 MHz, DMSO‑d6) spectrum of 3-(4-methox-
yphenyl)-2-thioxo-2,3-dihydro-quinazolin-4(1H)-one [40] since the
carbonyl at C-4 appears at δc 160.40 ppm and the thiocarbonyl group at
2. Results and discussion
2.1. Chemistry
3-Substituted 2-thioxo-2,3-dihydro-1H-quinazolin-4-ones 4a–e were
synthesized by one-pot-reaction of 2-aminobenzoic carboxylic acid (1)
and the appropriate alkyl/aryl isothiocyanates 2a–e in refluxing
Scheme 1. Synthesis of the target compounds 4a-e and 5a-o.
2

A.I. Khodair, et al.
CarbohydrateResearch486(2019)107832
Scheme 2. Synthesis of the target compounds 8a-j and 9a-h.
C-2 appears at δC 176.80 ppm. Furthermore, data from the elemental
analyses have been found to conform to the assigned structure. Also, the
molecular ion recorded in the mass spectrum is also in agreement with
the molecular weight of the compound. 1H NMR (500 MHz, DMSO‑d6)
spectrum of compound 5k showed a singlet at 3.31 ppm assigned to
N3CH3, a singlet at 3.43 ppm assigned to OCH3, a triplet at δH 3.59 ppm
(J = 6.25 Hz) assigned to SCH 2, a singlet at 3.67 ppm assigned to
OCH3, a triplet at 3.64 ppm (J = 6.25 Hz) assigned to the OCH2, a tri-
plet at δH 7.38 ppm (J = 7.25 Hz) assigned to 6-H, a doublet at
7.45 ppm (J = 7.00 Hz) assigned to 8-H, a triplet at δH 7.71 ppm
(J = 6.50 Hz) assigned to 7-H and a doublet at δH 8.06 ppm assigned to
5-H. The 13C NMR (500 MHz, DMSO‑d6) spectrum of 5k showed a
singlet at δC 157.20 ppm and 162.10 ppm assigned to –N]C–S– at C-2
and the carbonyl group at C-4, respectively, indicated that the site of
the alkylation is the sulfur atom rather than the nitrogen atom. These
data are also in agreement with the 13C NMR (300 MHz, DMSO‑d6)
spectrum of 3-ethyl-2-[2-(4-methoxyphenyl)-2-oxo-ethylthio]quina-
zolin-4(3H)-one [32], since –N]C–S– at C-2 appears at δc 153.40 ppm,
and the carbonyl group at C-4 appears at δC 160.60 ppm.
thioxo-4-thiazolidinones 6a-e, which in turn were treated with 2,3,4,6-
tetra-O-acetyl-α-D-glucopyranosyl bromide (7a) or 2,3,4,6-tetra-O-
acetyl-α-D-galactopyranosyl bromide (7b) to afford the S-glycosylated
nucleosides 8a–j in good yields (54–91%), (Scheme 2). Thin layer
chromatography (CH2Cl2/MeOH, 98:2) indicated the formation of pure
compounds. The structures of the S-glycoside 8a–j were confirmed by
elemental analysis and spectral data (IR, 1H NMR, 13C NMR). The 1H
NMR (500 MHz, CDCl3) spectrum of compound 8a as an example,
showed the anomeric proton of the glucose moiety as a doublet at
δ5.99 ppm with a coupling constant 2J 1’,2’ = 10.50 Hz indicating β-
configuration of the anomeric center. The other protons of the gluco-
pyranose ring resonated at δ3.98–5.42 ppm, while the four acetoxy
groups appeared as four singlets at δ1.92–2.00 ppm. The 13C NMR
(500 MHz, CDCl3) revealed the absence of the thione carbon atom at
about 175.85 ppm and the resonance of –N]C–N– carbon atom (C-2) at
δ153.04 ppm was indicated to the chemical shift of the corresponding
carbon atom (Fig. 1).
The signals at δ, 169.00, 170.00, 171.00 ppm were due to the four
acetoxy carbonyl atoms (4C]O), and the six signals at δ 61.97, 68.40,
68.80, 74.09, 76.46, 82.29 ppm were assigned to C-6′,C-2, C-3′, C-4′, C-
5′, and C-1′, respectively. Moreover, the IR spectra of compounds 8a-j
revealed the absence of the stretching signal of a thione group. These
The key intermediates for the synthesis of cyclic thioglycosides are
shown in Scheme 2. Analogously, Treatment of 3a-f with 1.1 equiva-
lents of NaH in anhydrous acetonitrile furnished the sodium salts of 2-
3

A.I. Khodair, et al.
CarbohydrateResearch486(2019)107832
Fig. 1. The chemical shift of the corresponding carbon atom at position 2 in 4a, 9a, and 5k.
data are also in agreement with the 13C NMR (DMSO‑d6) spectrum of 7-
(4-chlorophenyl)-5-phenyl-2-(2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyr-
anosylthio)pyrido [2,3-d]pyrimidine-4-one [34] since the carbonyl at
C-4 appears at δC163.20 ppm and –N]C–N– carbon atom (C-2) appears
at δC152.20.8 ppm, indicating the presence of S-glycosylation.
Removal of the acetyl groups from the glycon moiety of 8a-e and
8g-j with a saturated 5% NH3/MeOH solution at room temperature
furnished the corresponding free nucleosides 9a-e and 9f-h, respec-
tively (Scheme 2). The structures of 9a were confirmed by their spec-
troscopic and mass spectral data. The mass spectrum of 9a showed a
molecular ion peak at m/z = 354, while the 1H NMR spectrum showed
a doublet at δH 5.50 with J1',2' = 12.00 Hz, corresponding to the 1′-H
and indicating a β-configuration. C-2 of 9a resonated at δC153.31 ppm,
establishing the S-glycosylation. Furthermore, the heteronuclear
spectra (HMQC, DFQ-COSY) of 9a-h no such correlation was shown
between C-8a and 1′-H, which is an indication of the S-glycosylation.
The nucleoside bases 4 can be utilized as starting materials for the
synthesis of other carbohydrate derivatives as deoxy, amino and azido
nucleosides.
was found that the treatment of the compounds was safe (non-toxic)
because there was a slight decrease in the percentage of cell survival.
These results proved the safety of the treatments of the compounds
towards noncancerous cells.
In the present study, we conclude the incorporation of sugar portion
to the nucleus, enhanced the cytotoxic activity against the MCF-7 and
HepG2 cell lines by having lower IC50 values, as shown in Table 2.
Although both compounds 9a and 9c have near IC50 values (2.09 and
2.04 μM, respectively) against HepG2 cells, 9a was considered as the
lead compound in our study according to the molecular docking results.
It has a higher binding affinity towards the EGFR tyrosine kinase re-
ceptor because it forms larger number of hydrogen bonds with the key
amino acid residue Met 769 compared to other derivatives, so it was
selected for further testing as the molecular mode of action. An attempt
to study the structure-activity relationship using the molecular docking
tool for elucidation the binding interactions of the nucleosides which
might justify their higher potency.
2.4. Apoptotic assay
2.2. Molecular docking studies
Based on the high binding affinity of the analyzed derivatives
especially compound 9a towards EGFR tyrosine kinase receptor
through the molecular modeling analysis, and the significant cytotoxic
activity of 9a (IC50 = 2.09 μM), it was thought worthwhile to further
investigate its effect on induction of apoptosis in HepG2 cancer cells for
investigation the apoptotic pathway. HepG2 cells were treated with
50 μM of the compound for 48 h after this RNA was extracted, cDNA
was synthesized, and RT-PCR reaction was made to follow the mRNA
expression of apoptosis-related genes; pro-apoptotic P53, MDM2,
PUMA and Bax in the 9a-treated HepG2 cells. It is well known that the
upregulation of the pro-apoptotic genes is a sign for the modulation of
cell death.
All synthesized derivatives were subjected to molecular docking
studies, in which their binding affinities were studied as EGFR activity.
Molecular docking calculations concluded that among the docked de-
rivatives, only some of them had nearly the same binding mode of in-
teractions as the co-crystallized ligand inside the receptor binding site.
In this part, the ligand-receptor interactions for the promising com-
pounds which have the same EGFR activity were provided.
Table 1 and Fig. 2, summarize the ligand-receptor interactions in-
side the 1M17 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 5n, 8c, 8g, 9c and especially 9a
might have the same EGFR activity as the co-crystallized ligand where
they form the same interactions with Met 769 which is the key amino
acid interactions for the EGFR activity Fig. 2A. So, these derivatives
were worthy of being further tested against different cancer cell lines to
collect an overview of their biological activity.
As shown in Fig. 4, Compound 9a significantly activated the level of
P53 gene (with a maximum increase of ≈3.1-fold, P ≤ 0.001). The
compound was able to significantly increase the mRNA levels of all the
p53 target genes: PUMA (with a maximum increase of ≈8.03-fold,
P ≤ 0.001), and MDM2 (with a maximum increase of ≈2.6-fold,
P ≤ 0.05). Then, the expression of another gene that is correlated to
p53 reactivation was investigated. The expression of the pro-apoptotic
“multi-domain” Bcl-2 family member BAX was assessed by RT-PCR
analysis. As expected, the compound treatment of the HepG2 cells
caused a significant increase in BAX (maximum increase of ≈1.9-fold,
P ≤ 0.05). The results are in accordance with the proposed apoptotic
pathway for anti-cancer activity.
2.3. In vitro cytotoxic activity
Anti-cancer activity of the promising derivatives 5n, 8c, 8g, 9c, and
9a was tested against breast (MCF-7), liver (HepG2) cell lines by
measuring the percentage of cell survival against their serial dilutions
(0.01, 0.1, 1, 10, and 100 μM). Moreover, they were screened against
the GMSC as normal cell line to test their safety.
3. Experimental
As shown in Fig. 3, the percentage of cell survival relative to control
decreases with increasing concentrations proving their cytotoxic ac-
tivities. It decreased in a dose-response curve that means with in-
creasing concentrations percentage of cell survival decreased, except in
some treatments due to some variation in the biological behavior of
cells. Moreover, some of the analyzed compounds exhibited a sub-
stantial decrease in the percentage of cell survival than the standard
drug itself. For the cytotoxic activity against the normal GMSC cells, it
3.1. General procedures
All melting points were taken on the Electrothermal IA 9100 series
digital melting point apparatus. Microanalytical data (in accord with
the calculated values) were performed by Vario, Elementar apparatus
(Shimadzu). The IR spectra (KBr) were recorded on a Perkin–Elmer
1650 spectrometer (USA). 1H NMR and13
C NMR spectra were
4

A.I. Khodair, et al.
CarbohydrateResearch486(2019)107832
determined on a JEOL ECA-500. Chemical shifts were expressed in ppm
relative to SiMe4 as internal standards and DMSO-d6or CDCl3 or CD3OD
as a solvent. Mass spectra were recorded on70 eV EI Ms-QP 1000 EX
(Shimadzu).
3.2. Synthesis
3-Substituted 2-thioxo-2,3-dihydro-1H-quinazolin-4-ones (4a-
e).
To a mixture of 2-aminobenzoic acid (1) (1.37 g, 10 mmol), anhy-
drous triethylamine (2.00 mL, 22.22 mmol) and anhydrous ethanol
(50 mL) was added the appropriate alkyl/aryl isothiocyanates 2a–e
(11 mmol). The mixture was refluxed until the starting material was
consumed (4 h; TLC, ethyl acetate/methanol, 99.9:0.1) and cooled at
room temperature. The reaction mixture was diluted with water and
neutralized with diluted hydrochloric acid. The solid separated was
collected by filtration and recrystallized from ethanol to give the pro-
ducts 4a-e in quantitative yields.
3-Methyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one
(4a):Yield:1.75 g (91%), mp: 244–246 °C (270–272 °C [41]). MS:m/z:
192 (M+, 100%). Calculated for C9H8N2OS (192.24): C, 56.23; H, 4.19;
N, 14.57. Found: C, 56.02; H, 4.38; N, 14.26. IR (KBr): ν 3176 (NH),
1622 (C]O), 1289 (C]S) cm−1.1H NMR (500 MHz, DMSO‑d6):
δ = 3.60 (3H, s, CH3), 7.33(1H, t, J = 7.50 Hz, H-6), 7.39(1H, d,
J = 8.50 Hz, H-8), 7.74 (1H, t, J = 7.50 Hz, H-7), 7.94 (1H, d,
J = 8.00 Hz, H-5), 12.80 (1H, s, NH)·13C NMR (500 MHz, DMSO‑d6):
δ = 33.70 (CH3), 115.76 (C-6), 116.07 (C-8), 124.28 (C-5), 127.70 (C-
7), 135.76 (C-4a), 139.55 (C-8a), 160.08 (C-4), 175.85 (C-2).
3-Ethyl-2-thioxo-2,3-dihydroquinazolin-4(H)-one (4b): Yield:1.76 g
(85%), mp: 246–248 °C (290–291 °C [42]). MS:m/z: 206 (M+, 84%). Cal-
culated for C10H10N2OS (206.27): C, 58.23; H, 4.89; N, 13.58. Found: C,
58.12; H, 4.98; N, 13.37. IR (KBr): ν 3247 (NH), 1651 (C]O), 1285 (C]S)
cm−1.1H NMR (500 MHz, DMSO‑d6): δ = 1.23 (3H, t, J = 6.50.00 Hz,
CH3), 4.46 (2H, q, J = 7.00 Hz, CH2), 7.33 (1H, t, J = 7.50 Hz, H-6), 7.39
(1H, d, J = 8.50 Hz, H-8), 7.74 (1H, t, J = 7.25 Hz, H-7), 7.90 (1H, d,
J = 7.50 Hz, H-5), 13.00 (1H, s, NH). 13C NMR (500 MHz, DMSO‑d6):
δ = 12.40 (CH2CH3), 41.45 (CH2CH3), 116.02 (C-6), 116.06 (C-8), 124.90
(C-5), 127.67 (C-7), 135.84 (C-4a), 139.52 (C-8a), 159.49 (C-4), 175.30 (C-
2).
3-Allyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one
(4c):Yield:
1.82 g (83%), mp: 184–186 °C (180–182 °C [42]). MS:m/z: 218 (M+
,
7%). Calculated for C11H10N2OS (218.28): C, 60.53; H, 4.62; N, 12.83.
Found: C, 60.38; H, 4.84; N, 12.60. IR (KBr): ν 3159 (NH), 1654 (C]O),
1262 (C]S) cm−1.1H NMR (500 MHz, DMSO‑d6): δ = 5.03 (2H, d,
J = 4.85 Hz, H-1allyl), 5.15 (1H, m, H-3allyl), 5.91 (1H, m, H-2allyl),7.30
(1H, t, J = 7.25 Hz, H-6), 7.38 (1H, d, J = 8.50 Hz, H-8), 7.71 (1H, t,
J = 7.00 Hz, H-7), 7.90 (1H, d, J = 7.50 Hz, H-5), 12.80 (1H, s, NH).
13C NMR (500 MHz, DMSO‑d6): δ = 48.03 (C1-allyl), 115.88 (C3-allyl),
116.61 (C-6), 117.61 (C-8), 124.84 (C-5), 127.69 (C-7), 132.29 (C2-
allyl), 135.83 (C-4a), 139.62(C-8a), 159.45(C-4), 175.54 (C-2).
3-Phenyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one
(4d):
Yield:2.23 g (88%), mp: 290–292 °C (160–165 °C, 305–307 °C [43–45],
300–320 °C [46]). MS:m/z: 254 (M+, 53%). Calculated for C14H10N2OS
(254.31): C, 66.12; H, 3.96; N, 11.02. Found: C, 65.87; H, 4.05; N,
10.78. IR (KBr): ν 3214 (NH), 1662 (C]O), 1289 (C]S) cm−1.1H NMR
(500 MHz, DMSO‑d6): δ = 7.28 (2H, d, J = 7.50 Hz, H-2′, H-6′), 7.30
(1H, t, J = 7.50 Hz, H-6), 7.41 (1H, d, J = 7.50 Hz, H-8), 7.47 (3H, m,
H-4′, H-3′,H-5′), 7.78 (1H, t, J = 7.50 Hz, H-7), 7.95 (1H, d,
J = 7.50 Hz, H-5), 13.00 (1H, s, NH). 13C NMR (500 MHz, DMSO‑d6):
δ = 116.18 (C-6), 116.66 (C-8), 124.78 (C-5), 127.88 (C-7), 128.56(C-
4′), 129.35(C-2′, C-6′), 129.48 (C-3′, C-5′), 136.03 (C-1′), 139.78 (C-4a),
140.096 (C-8a), 160.27 (C-4), 176.58 (C-2).
3-(4-Methoxyphenyl)-2-thioxo-2,3-dihydroquinazolin-4(1H)-
one (4e): Yield 2.32 g (82%), mp: 240–242 °C, (178–280 °C [47]).
MS:m/z: 284 (M+, 5%). Calculated for C15H12N2O2S (284.33): C, 63.36;
H, 4.25; N, 9.85. Found: C, 63.14; H, 4.42; N, 9.63. IR (KBr): ν 3243
5

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CarbohydrateResearch486(2019)107832
Fig. 2. Binding modes of the co-crystallized ligand (A) and the docked compounds 5n, 8c, 8g, 9c and 9a (B–F), receptively, and their molecular interactions to the
1M17 binding site.
(NH), 1661 (C]O), 1300 (C]S) cm−1.1H NMR (500 MHz, DMSO‑d6):
δ = 3.81 (3H, s, OCH3), 7.00 (2H, d, J = 8.50 Hz, H-3′, H-5′), 7.16 (2H,
d, J = 7.00 Hz, H-2′, H-6′), 7.31 (1H, t, J = 7.50 Hz, H-6), 7.42 (1H, d,
J = 8.00 Hz, H-8), 7.74 (1H, t, J = 7.50 Hz, H-7), 7.93 (1H, d,
J = 7.50 Hz, H-5), 12.80 (1H, s, NH). 13C NMR (500 MHz, DMSO‑d6):
δ = 55.75 (OCH3), 114.51 (C-2′, C-6′), 116.82 (C-6), 116.91 (C-8),
6

A.I. Khodair, et al.
CarbohydrateResearch486(2019)107832
Fig. 3. Cytotoxic activity of the analyzed compounds against breast (MCF-7), liver (HepG2) cell lines, and normal cell line (GMSC).
Table 2
Summarized IC50 for the activity of the analyzed compounds against the MCF-7
and HepG2 cell lines.
IC50 (μM)
MCF-7
HepG2
GMSC
5-FU
5n
4.23
8.96
5.93
2.42
2.04
2.09
4.43
1.52
3.79
1.17
2.09
2.08
˃ 50
˃ 50
˃ 50
ND
8c
8 g
9c
˃ 50
˃ 50
9a
ND= Not Determined.
124.38 (C-5), 127.78 (C-7), 128.56 (C-3′, C-5′), 130.45(C-1′), 132.75
(C-4a), 135.75 (C-8a), 140.99 (C-4′), 160.68 (C-4), 176.90 (C-2).
Fig. 4. RT-PCR analysis of the p53 mRNA and p53-related genes was performed
after the HepG2 cells were treated with Compound 9a (50 μM) for 48 h. Signs of
* and *** mean values are significantly (P ≤ 0.05) and highly significant
(P ≤ 0.001) different using unpaired t-test (GraphPad Prism).
3-Substituded
2-ethylsulfanyl-2,3-dihydroquinazolin-4(H)-
ones (5a-e): A mixture of 3-substituded-2-thioxo-2,3-dihydro-1H-qui-
nazolin-4-ones (4a-e) (1 mmol), anhydrous acetonitrile (10 mL) and
sodium hydride (45 mg, 80%) was stirred at room temperature 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 (8 h; TLC,
ethyl acetate/hexane, 30:70) and cooled at room temperature. 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 5a-e in quantita-
tive yields.
J = 7.50 Hz, H-6), 7.52 (1H, d, J = 8.00 Hz, H-8), 7.76 (1H, t,
J = 7.50 Hz, H-7), 8.06 (1H, d, J = 7.50 Hz, H-5).13C NMR (500 MHz,
DMSO‑d6): δ = 14.37 (SCH2CH3), 26.37 (SCH2CH3), 26.37 (N3–CH3),
119.04 (C-6), 126.29 (C-8), 126.70 (C-5), 126.83 (C-7), 134.93 (C-4a),
147.39 (C-8a), 157.57 (C-2), 161.21 (C-4).
3-Ethyl-2-ethylsulfanyl-2,3-dihydroquinazolin-4(H)-one (5b):
Yield: 0.23 g (62%), mp: 37–39 °C [173–174 °C [41]). MS: m/z: 234
(M+, 100%). Calculated for C12H14N2OS (234.32): C, 61.51; H, 6.02; N,
11.96. Found: C, 61.34; H, 6.44; N, 11.67. IR (KBr): ν 1679 (C]O)
cm−1.1H NMR (500 MHz, DMSO‑d6): δ = 1.25 (3H, t, J = 7.00 Hz,
SCH2CH3), 1.37 (3H, t, J = 7.25 Hz, NCH2CH3), 3.27 (2H, q,
J = 7.25 Hz, SCH2CH3), 4.07 (2H, q, J = 6.75 Hz, NCH2CH3), 7.43 (1H,
3-Methyl-2-ethylsulfanyl-2,3-dihydroquinazolin-4(1H)-one
(5a): Yield: 0.21 g (95%), mp: 65–67 °C. MS: m/z: 220 (M+, 1%).
Calculated for C11H12N2OS (220.29): C, 59.97; H, 5.49; N, 12.72.
Found: C, 60.14; H, 5.60; N, 12.38. IR (KBr): ν 1685 (C]O) cm−1.1H
NMR (500 MHz, DMSO‑d6): δ = 1.37 (3H, t, J = 6.75 Hz, SCH2CH3),
3.27 (2H, q, J = 7.00 Hz, SCH2CH3), 3.48 (3H, s, N3–CH3), 7.42 (1H, t,
7

A.I. Khodair, et al.
CarbohydrateResearch486(2019)107832
t, J = 7.50 Hz, H-6), 7.51 (1H, d, J = 8.00 Hz, H-8), 7.76 (1H, t,
J = 7.50 Hz, H-7), 8.06 (1H, d, J = 7.50 Hz, H-5). 13C NMR (500 MHz,
DMSO‑d6): δ = 13.43 (SCH2CH3), 14.14 (N3CH2CH3), 26.33
(SCH2CH3), 39.57 (N3CH2CH3), 119.29 (C-6), 126.20 (C-8), 126.33 (C-
5), 126.77 (C-7), 135.02 (C-4a), 147.39 (C-8a), 156.68 (C-2), 160.82
(C-4).
(C-2), 161.70 (C-4), 168.50 (COO).
(3-Ethyl-4-oxo-3,4-dihydroquinazolin-2-ylsulfanyl)-acetic acid
ethyl ester (5g): Yield: 0.20 g (83%), mp: 64–66 °C. MS: m/z: 292 (M+
,
4%). Calculated for C14H16N2O3S (292.35): C, 57.52; H, 5.52; N, 9.58.
Found: C, 57.35; H, 5.58; N, 9.26. IR (KBr): ν 1738 (COO), 1684 (C]O)
cm−1.1H NMR (500 MHz, CDCl3): δ = 1.32 (3H, t, J = 7.25 Hz,
N3CH2CH3), 1.43 (3H, t, J = 7.00 Hz, OCH2CH3), 4.05 (2H, s,
SCH2COO), 4.25 (4H, m, N3–CH2, OCH2CH3), 7.39 (1H, t, J = 7.25 Hz,
H-6), 7.40 (1H, d, J = 8.00 Hz, H-8), 7.68 (1H, d, J = 6.75 Hz, H-7),
8.22 (1H, d, J = 7.00 Hz, H-5). 13C NMR (500 MHz,CDCl3): δ = 13.29
(N3CH2CH3), 14.25 (OCH2CH3), 34.48 (SCH2COO), 39.95 (N3CH2CH3),
61.89 (OCH2CH3), 119.50 (C-6), 125.86 (C-8), 125.99 (C-5), 126.93 (C-
7), 134.23 (C-4a), 147.19 (C-8a), 154.80 (C-2), 161.40 (C-4), 168.60
(COO).
3-Allyl-2-ethylsulfanyl-2,3-dihydroquinazolin-4(1H)-one (5c):
Yield: 0.22 g (89%), pale yellow oil. MS: m/z: 246 (M+, 20%).
Calculated for C13H14N2OS (246.33): C, 63.39; H, 5.73; N, 11.37.
Found: C, 63.05; H, 5.96; N, 11.11. IR (KBr): ν 1676 (C]O) cm−1.1H
NMR (500 MHz, DMSO‑d6): δ = 1.48 (t, J = 6.75 Hz, SCH2CH3), 3.35
(2H, q, J = 7.25 Hz, SCH2CH3), 4.80 (2H, d, J = 4.85 Hz, H-1allyl), 5.27
(2H, m, H-3allyl), 6.02 (1H, m, H-2allyl), 7.41 (1H, t, J = 7.50 Hz, H-6),
7.50 (1H, d, J = 8.00 Hz, H-8), 7.77 (1H, t, J = 7.50 Hz, H-7), 8.04 (1H,
d, J = 7.50 Hz, H-5). 13C NMR (500 MHz, DMSO‑d6): δ = 14.02
(SCH2CH3), 26.72 (SCH2CH3), 46.37 (C-1allyl), 118.23 (C-3allyl), 118.84
(C-6), 126.25 (C-8), 126.36 (C-5), 126.78 (C-7), 131.32 (C-2allyl),
135.06 (C-4a), 147.38 (C-8a), 156.69 (C-2), 160.87 (C-4).
(3-Allyl-4-oxo-3,4-dihydroquinazolin-2-ylsulfanyl)-acetic acid
ethyl ester (5h): Yield: 0.30 g (86%), mp: 52–54 °C. MS: m/z: 304 (M+
,
0.01%). Calculated for C15H16N2O3S (304.37): C, 59.19; H, 5.30; N,
9.20. Found: C, 59.01; H, 5.49; N, 8.88. IR (KBr): ν 1743 (COO), 1685
(C]O) cm−1.1H NMR (500 MHz, DMSO‑d6): δ = 1.21 (3H, t,
J = 7.00 Hz, OCH2CH3), 4.12 (6H, s, SCH2COO), 4.15 (2H, q,
J = 7.75 Hz, OCH2CH3), 4.70 (2H, d,J = 7.75 Hz, NCH2CH]CH2), 5.20
(2H, m, NCH2CH]CH2), 5.93 (1H, m, NCH2CH]CH2), 7.42 (1H, t,
J = 7.25 Hz, H-6), 7.46 (1H, d, J = 8.00 Hz, H-8), 7.79 (1H, d,
J = 7.25 Hz, H-7), 8.07 (1H, d, J = 7.50 Hz, H-5). 13C NMR (500 MHz,
DMSO‑d6): δ = 14.59 (OCH2CH3), 34.53 (SCH2COO), 46.34 (C-1allyl),
61.55 (OCH2CH3), 118.40(C-3allyl), 119.11 (C-6), 126.20 (C-8), 126.57
(C-5), 126.98 (C-7), 131.70 (C-2allyl), 135.30 (C-4a), 147.06 (C-8a),
156.40 (C-2), 160.40 (C-4), 168.70 (COO).
3-Phenyl-2-ethylsulfanyl-2,3-dihydroquinazolin-4(1H)-one
(5d): Yield: 0.27 g (96%), mp: 96–98 °C. MS: m/z: 282 (M+, 6%).
Calculated for C16H14N2OS (282.36): C, 68.06; H, 5.00; N, 9.92. Found:
C, 67.85; H, 5.18; N, 9.78. IR (KBr): ν 1662 (C]O) cm−1.1H NMR
(500 MHz, DMSO‑d6): δ = 1.27 (t, J = 7.25 Hz, SCH2CH3), 3.12 (2H, q,
J = 7.25 Hz, SCH2CH3),7.08 (2H, d, J = 8.50 Hz, H-2′, H-6′), 7.34 (1H,
t, J = 8.50 Hz, H-6), 7.46 (3H, m, H-3′, H-4′, H-5′), 7.60 (1H, d,
J = 8.00 Hz, H-8), 7.82 (1H, t, J = 7.50 Hz, H-7), 8.07 (1H, d,
J = 7.50 Hz, H-5). 13C NMR (500 MHz, DMSO‑d6): δ = 14.23
(SCH2CH3), 26.76 (SCH2CH3), 120.01 (C-6), 126.31 (C-8), 126.51 (C-
5), 127.00 (C-7), 129.86 (C-4′), 129.88 (C-2′, C-6′), 130.19 (C-3′, C-5′),
135.34 (C-1′), 136.49 (C-4a), 147.80 (C-8a), 157.82 (C-2), 161.23 (C-
4).
(3-Phenyl-4-oxo-3,4-dihydroquinazolin-2-ylsulfanyl)-acetic
acid ethyl ester (5i): Yield: 0.30 g (94%), mp: 98–100 °C. MS: m/z: 340
(M+, 14%). Calculated for C18H16N2O3S (390.46): C, 63.51; H, 4.74; N,
8.23. Found: C, C, 63.23; H, 4.92; N, 8.07. IR (KBr): ν 1739 (COO), 1694
(C]O) cm−1.1H NMR (500 MHz, DMSO‑d6): δ = 1.22 (3H, t,
J = 7.00 Hz, OCH2CH3), 3.98 (2H, s, SCH2COO), 4.10 (2H, q,
J = 6.75 Hz, OCH2CH3), 7.48 (4H, m, H-2′, H-6′, H-6, H-8), 7.59 (3H,
m, H-4′, H-3′, H-5′), 7.84 (1H, t, J = 7.00 Hz, H-7), 8.09 (1H, d,
J = 7.50 Hz, H-5). 13C NMR (500 MHz, DMSO‑d6): δ = 14.60
(OCH2CH3), 34.88 (SCH2COO), 61.50 (OCH2CH3), 119.96 (C-6), 126.36
(C-8), 126.61 (C-5), 127.09 (C-7), 129.84 (C-4′), 130.05 (C-2′, C-6′),
130.52 (C-3′, C-5′), 135.47 (C-1′), 136.16(C-4a), 147.49 (C-8a), 157.00
(C-2), 161.00 (C-4), 168.80 (COO).
3-(4-Methoxyphenyl)-2-ethylsulfanyl-2,3-dihydroquinazolin-
4(1H)-one (5e): Yield: 0.25 g (80%), mp: 142–144 °C. MS: m/z: 312
(M+, 6%). Calculated for C17H16N2O2S (312.39): C, 65.36; H, 5.16; N,
8.97. Found: C, 65.17; H, 5.30; N, 8.01. IR (KBr): ν 1685 (C]O)
cm−1.1H NMR (500 MHz, DMSO‑d6): δ = 1.27 (t, J = 7.25 Hz,
SCH2CH3), 3.10 (2H, q, J = 7.25 Hz, SCH2CH3), 3.84 (1H, s, OCH3),
7.42(2H, d, J = 7.00 Hz, H-2′, H-6′), 7.43 (1H, t, J = 7.50 Hz, H-6),
7.48 (2H, d, J = 7.00 Hz, H-3′, H-5′), 7.60 (1H, d, J = 7.50 Hz, H-8),
7.80 (1H, t, J = 7.00 Hz, H-7), 8.06 (1H, d, J = 7.50 Hz, H-5). 13C NMR
(500 MHz, DMSO‑d6): δ = 14.19 (SCH2CH3), 26.73 (SCH2CH3), 55.93
(OCH3), 115.04 (C-2′, C-6′), 120.01 (C-6), 126.22 (C-8), 126.48 (C-5),
127.03 (C-7), 128.91 (C-3′, C-5′), 131.04 (C-1′), 135.24 (C-4a), 147.85
(C-8a), 158.53 (C-2), 160.45 (C-4′), 161.42 (C-4).
(3-(4-Methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylsul-
fanyl)-acetic acid ethyl ester (5j): Yield: 0.34 g (65.50%), mp:
138–140 °C. MS: m/z: 370 (M+, 23%). Calculated for C19H18N2O4S
(390.46): C, 61.61; H, 4.90; N, 7.56. Found: C, C, 72.61; H, 4.98; N,
7.43. IR (KBr): ν 1735 (COO), 1687 (C]O) cm−1.1H NMR (500 MHz,
CDCl3): δ = 1.32 (3H, t, J = 6.50 Hz, OCH2CH3), 3.91 (2H, s,
SCH2COO), 4.24 (2H, q, J = 7.00 Hz, OCH2CH3), 7.07 (2H, d,
J = 8.00 Hz, H-2′, H-6′), 7.29 (2H, d, J = 8.50 Hz, H-3′, H-5′), 7.43 (1H,
t, J = 6.70 Hz, H-6), 7.56 (1H, d, J = 7.50 Hz, H-8), 7.73 (1H, t,
J = 8.50 Hz, H-7), 8.24(1H, d, J = 6.50 Hz, H-5). 13C NMR (500 MHz,
CDCl3): δ = 14.28 (OCH2CH3), 35.00 (SCH2COO), 61.77 (OCH2CH3),
115.04 (C-2′, C-6′), 119.90 (C-6), 126.01 (C-8), 126.20 (C-5), 127.30
(C-7), 128.01 (C-3′, C-5′), 130.04 (C-1′), 134.06 (C-4a), 147.56 (C-8a),
156.66 (C-2), 160.70 (C-4′), 161.90 (C-4), 168.70 (COO).
(3-Substituded
4-oxo-3,4-dihydroquinazolin-2-ylsulfanyl)-
acetic acid ethyl esters (5f-j):
A mixture of 4a-e (1 mmol), anhydrous acetonitrile (10 mL) and
sodium hydride (45 mg, 80%) was stirred at room temperature for ½
hour. Ethylbromoacetate (0.33 g, 2 mmol) was added to the mixture
with stirring at 40–50 °C until the starting material was consumed (8 h;
TLC, ethyl acetate/hexane, 30:70) and cooled at room temperature. The
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 5f-j in quantitative
yields.
(3-Methyl-4-oxo-3,4-dihydroquinazolin-2-ylsulfanyl)-acetic
acid ethyl ester (5f): Yield: 0.17 g (61%), mp: 70–72 °C. MS: m/z: 278
(M+, 18%). Calculated for C13H14N2O3S (278.33): C, 56.10; H, 5.07; N,
10.06. Found: C, 55.95; H, 5.35; N, 9.87. IR (KBr): ν 1733 (COO), 1674
(C]O) cm−1.1H NMR (500 MHz, CDCl3): δ = 1.32 (3H, t, J = 7.00 Hz,
OCH2CH3), 3.64 (3H, s, N3–CH3), 4.04 (2H, s, SCH2COO), 4.26 (2H, t,
J = 7.25 Hz, OCH2CH3), 7.37 (1H, t, J = 7.00 Hz, H-6), 7.49 (1H, d,
J = 8.00 Hz, H-8), 7.67 (1H, t, J = 6.75 Hz, H-7), 8.21 (1H, d,
J = 7.00 Hz, H-5). 13C NMR (DMSO‑d6): δ = 14.25 (OCH2CH3), 30.36
(N3–CH3), 34.54 (SCH2COO), 61.92 (OCH2CH3), 119.15 (C-6), 125.85
(C-8), 125.99 (C-5), 126.98 (C-7), 134.24 (C-4a), 147.15 (C-8a), 155.50
3-Substituded 2-ethoxymethylsulfanyl-2,3-dihydro-1H-quina-
zolin-4-ones (5k-o):
A mixture of 4a-e (5 mmol), anhydrous dimethylformamide (10 mL)
and potassium carbonate (0.83 g, 6 mmol) was stirred at room tem-
perature for ½ hour.1-Chloro-2-rmethoxyethane (0.54 g, 6 mmol) was
added to the mixture with stirring 90–100 °C until the starting material
was consumed (2 h; TLC, ethyl acetate/hexane, 50:50) and cooled at
room temperature. The mixture was poured into cold water and the
separated was collected by filtration and recrystallized from cyclo-
hexane to give the products 5k-o in quantitative yields.
3-Methyl-2-ethoxymethylsulfanyl-2,3-dihydroquinazolin-
8

A.I. Khodair, et al.
CarbohydrateResearch486(2019)107832
4(1H)-one (5k): Yield: 1.00 g (80%), mp: 40–42 °C. MS: m/z: 250 (M+
,
acetonitrile (25 mL) at room temperature. To this suspension 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-glyco-
pyranosyl bromides (7a,b, 2.66 g, 5.50 mmol) was added, and the
mixture was stirred at room temperature for 12 h until the starting
material was consumed (TLC, CH2Cl2/MeOH, 98:2). The solvent was
removed under reduced pressure and then treated with water. The solid
separated was collected by filtration and recrystallized from ethanol to
give the products 8a-j in quantitative yields.
1%). Calculated for C12H14N2O2S (250.32): C, 57.58; H, 5.64; N, 11.19.
Found: C, C, 57.39; H, 5.58; N, 11.04. IR (KBr): ν 1675 (C]O) cm−1.1H
NMR (500 MHz, DMSO‑d6): δ = 3.31 (3H, s, N3CH3), 3.43 (3H, s,
OCH3), 3.43 (2H, t, J = 5.25 Hz, SCH 2), 3.64 (2H, t, J = 6.25 Hz,
OCH2), 7.38 (1H, t, J = 7.25 Hz, H-6), 7.45 (1H, d, J = 7.00 Hz, H-8),
7.71 (1H, t, J = 6.50 Hz, H-7), 8.06 (1H, d, J = 6.00 Hz, H-5). 13C NMR
(500 MHz, DMSO‑d6): δ = 30.42 (SCH 2), 31.42 (N3CH3), 58.38
(OCH3), 70.26 (OCH2), 118.98 (C-6), 126.03 (C-8), 126.04 (C-7),
126.77 (C-5), 134.79 (C-4a), 141.17 (C-8a), 157.20 (C-2), 162.10 (C-4).
3-Ethyl-2-ethoxymethylsulfanyl-2,3-dihydroquinazolin-4(1H)-
one (5l): Yield: 1.06 g (80%), mp: 38–40 °C. MS: m/z: 264 (M+, 1.6%).
Calculated for C13H16N2O2S (264.34): C, 59.07; H, 6.10; N, 10.60.
Found: C, 58.76; H, 6.35; N, 10.48. IR (KBr): ν 1680 (C]O) cm−1.1H
NMR (500 MHz, CDCl3): δ = 1.38 (3H, t, J = 6.25 Hz, N3CH2CH3), 3.52
(2H, q, J = 6.25 Hz, N3CH2CH3), 3.44 (3H, s, OCH3), 3.75 (2H, t,
J = 5.50 Hz, SCH 2), 4.22 (2H, t, J = 6.50 Hz, OCH2), 7.37(1H, t,
J = 7.00 Hz, H-6), 7.39(1H, d, J = 7.50 Hz, H-8), 7.66 (1H, t,
J = 6.50 Hz, H-7), 8.21(1H, d, J = 7.50 Hz, H-5). 13C NMR (500 MHz,
CDCl3): δ = 13.30 (N3CH2CH3), 31.48 (SCH 2), 39.70 (N3CH2CH3),
58.81 (OCH3), 70.70 (OCH2), 119.47 (C-6), 125.58 (C-8), 125.99 (C-5),
126.90 (C-7), 134.14 (C-4a), 147.40 (C-8a), 159.90 (C-2), 161.50 (C-4).
3-Allyl-2-ethoxymethylsulfanyl-2,3-dihydroquinazolin-4(1H)-
one (5m): Yield:1.00 g (72%), mp: 40–42 °C.MS: m/z: 376 (M+, 1.2%).
Calculated for C14H16N2O2S (326.41): C, 60.85; H, 5.84; N, 10.14.
Found: C, 60.64; H, 5.99; N, 10.00. IR (KBr): ν 1683 (C]O) cm−1.1H
NMR (500 MHz, CDCl3): δ = 3.44 (3H, s, OCH3), 3.50 (2H, t,
J = 6.00 Hz, SCH 2), 3.70 (2H, t, J = 5.00 Hz, OCH2), 4.80 (2H, d,
J = 5.00 Hz, N3CH2CH]CH2), 5.28 (2H, m, N3CH2CH]CH2), 5.96
(1H, m, N3CH2CH]CH2), 7.40 (1H, t, J = 7.00 Hz, H-6), 7.55 (1H, d,
J = 7.50 Hz, H-8), 7.68 (1H, t, J = 7.00 Hz, H-7), 8.23 (1H, d,
J = 7.00 Hz, H-5).13C NMR (500 MHz, CDCl3): δ = 31.64(SCH 2),
46.25 (N3–CH2CH]CH2), 58.85 (OCH3), 70.64 (OCH2), 118.56
(N3–CH2CH]CH2), 119.32 (C-6), 125.70 (C-8), 126.03 (C-5), 127.00
(C-7), 130.82 (N3–CH2CH]CH2), 134.32 (C-4a), 147.32 (C-8a), 156.10
(C-2), 161.50 (C-4).
3-Methyl-2-(2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyr-
anosylsulfanyl)-2,3-dihydroquinazol-in-4(1H)-one (8a): Yield:
2.00 g (77%), mp: 158–162 °C. MS: m/z: 522 (M+, 1%). Calculated for
C
23H26N2O10S (522.53): C, 52.87; H, 5.02; N, 5.36. Found: C, 52.59; H,
5.32; N, 5.17. IR (KBr): ν 1755 (C]O), 1698 (C]O) cm−1.1H NMR
(500 MHz, CDCl3): δ = 1.92 (3H, s, Ac), 1.98 (3H, s, Ac), 2.00 (3H, s,
Ac), 2.06 (3H, s, Ac), 3.57 (3H, s, N3CH3), 3.98 (1H, m, H-6′), 4.25 (2H,
m, H-5′, H-6″), 5.15 (1H, t, J = 9.50 Hz, 4′-H), 5.31 (1H, t,
J = 10.00 Hz, 2′-H), 5.42 (1H, t, J = 9.00 Hz, 3′-H), 5.99 (1H, d, 2J
1’,2’ = 10.50 Hz, 1′-H), 7.41 (1H, t, J = 7.00 Hz, H-6), 7.53 (1H, d,
J = 7.50 Hz, H-8), 7.71 (1H, t, J = 6.75 Hz, H-7), 8.22 (1H, d,
J = 7.00 Hz, H-5). 13C NMR (500 MHz, CDCl3): δ = 20.57 (4Ac), 30.39
(N3CH3), 61.97 (C-6′), 68.40 (C-2′), 68.80 (C-3′), 74.09 (C-4′), 76.46 (C-
5′), 82.29 (C-1′), 119.52 (C-6), 126.25 (C-5, C-8), 127.03 (C-7), 134.51
(C-4a), 147.10 (C-8a), 153.04 (C-2), 161.30 (C-4), 169.00, 170.00,
171.00 (4Ac).
3-Ethyl-2-(2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyr-
anosylsulfanyl)-2,3-dihydroquinazolin-4(1H)-one
(8b):
Yield:
1.90 g (71%), mp: 87–89 °C. MS: m/z: 536 (M+, 0.5%). Calculated for
C
24H28N2O10S (536.55): C, 53.72; H, 5.26; N, 5.22. Found: C, 53.64; H,
5.70; N, 5.03. IR (KBr): ν 1751 (C]O), 1694 (C]O) cm−1.1H NMR
(500 MHz, CDCl3): δ = 1.90 (3H, s, Ac), 1.98 (3H, s, Ac), 2.05 (3H, s,
Ac), 2.07 (3H, s, Ac), 1.35 (3H, t, J = 7.00 Hz, N3CH2CH3), 3.90 (1H, m,
H-6′), 4.20 (2H, m, H-5′, H-6″), 4.60 (2H, q, J = 7.00 Hz, N3CH2CH3),
5.16 (1H, t, J = 9.00 Hz, 4′-H), 5.31 (1H, t, J = 9.50 Hz, 2′-H), 5.42
(1H, t, J = 8.50 Hz, 3′-H), 5.98 (1H, d, 2J 1’,2’ = 10.00 Hz, 1′-H), 7.13
(1H, t, J = 7.00 Hz, H-6), 7.31 (1H, d, J = 8.50 Hz, H-8), 7.52 (1H, t,
J = 7.00 Hz, H-7), 7.70 (1H, d, J = 8.00 Hz, H-5). 13C NMR (500 MHz,
CDCl3): δ = 13.37 (N3CH2CH3), 20.58 (4Ac), 39.89 (N3CH2CH3), 62.00
(C-6′), 68.40 (C-2′), 68.91 (C-3′), 74.13 (C-4′), 76.47 (C-5′), 82.58 (C-
1′), 119.79 (C-6), 124.80 (C-5), 126.22 (C-5, C-8), 127.83 (C-7), 134.32
(C-4a), 147.09 (C-8a), 150.00 (C-2), 161.30 (C-4), 169.49, 170.07,
170.56 (4Ac).
3-Phenyl-2-ethoxymethylsulfanyl-2,3-dihydroquinazolin-
4(1H)-one (5n): Yield:1.40.00 g (90%), mp: 96–98 °C. MS: m/z: 312
(M+, 1%). Calculated for C17H16N2O2S (312.39): C, 65.36; H, 5.16; N,
8.97. Found: C, 65.07; H, 5.35; N, 8.71. IR (KBr): ν 1689 (C]O)
cm−1.1H NMR (500 MHz, CDCl3): δ = 3.40(3H, s, OCH3), 3.44 (2H, t,
J = 6.30 Hz, SCH 2), 3.70 (2H, q, J = 6.30 Hz, OCH2), 7.34 (2H, d,
J = 7.50 Hz, H-2′, H-6′), 7.43 (1H, t, J = 7.50 Hz, H-6), 7.56 (3H, m, H-
3′, H-4′, H-5′), 7.67 (1H, d, J = 8.00 Hz, H-8), 7.75 (1H, t, J = 8.00 Hz,
H-7), 8.20 (1H, d, J = 7.50 Hz, H-5). 13C NMR (500 MHz, CDCl3):
δ = 32.01 (SCH 2), 58.76 (OCH3), 70.58 (OCH2), 125.94 (C-6), 126.13
(C-8), 127.31 (C-5), 129.17 (C-7), 129.17 (C-4′), 129.75 (C-2′, C-6′),
130.01 (C-3′, C-5′), 134.71 (C-1′), 135.81 (C-4a), 147.58 (C-8a), 157.20
(C-2), 161.80 (C-4).
3-Allyl-2-(2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyr-
anosylsulfanyl)-2,3-dihydroquinazolin-4(1H)-one
(8c):
Yield:
1.89 g (70%), mp: 108–110 °C. MS: m/z: 548 (M+, 0%). Calculated for
C
25H28N2O10S (548.56): C, 54.74; H, 5.14; N, 5.11. Found: C, 54.52; H,
5.27; N, 4.88. IR (KBr): ν 1751 (C]O), 1694 (C]O) cm−1.1H NMR
(500 MHz, CDCl3): δ = 1.94 (3H, s, Ac), 1.97 (3H, s, Ac), 2.04 (3H, s,
Ac), 2.06 (3H, s, Ac), 3.98 (1H, m, H-6′), 4.25 (2H, m, H-5′, H-6″), 4.63
(2H, dd, J = 5.50, 11.50 Hz, H-1allyl), 4.80 (2H, dd, J = 5.50, 11.50 Hz,
H-3allyl), 5.15 (1H, t, J = 9.50 Hz, 4′-H), 5.27 (1H, t, J = 9.50 Hz, 2′-H),
5.41 (1H, t, J = 8.50 Hz, 3′-H), 5.90 (1H, m, H-2allyl), 5.96 (1H, d, 2J
1’,2’ = 10.00 Hz, 1′-H), 7.42 (1H, t, J = 7.00 Hz, H-6), 7.54 (1H, d,
J = 8.50 Hz, H-8), 7.73 (1H, t, J = 7.00 Hz, H-7), 8.20 (1H, d,
J = 8.00 Hz, H-5).13C NMR (500 MHz, CDCl3): δ = 20.55 (4Ac), 46.31
(C-1allyl), 61.98 (C-6′), 68.38 (C-2′), 68.87 (C-3′), 74.07 (C-4′), 76.47 (C-
5′), 82.71 (C-1′), 118.93 (C-3allyl), 119.68 (C-6), 126.27 (C-8), 126.34
(C-5), 127.17 (C-7), 130.46 (C-2allyl), 134.48 (C-4a), 147.09 (C-8a),
153.02 (C-2), 161.28 (C-4), 169.42, 170.06, 170.52 (4Ac).
3-(4-Methoxyphenyl)-2-ethoxymethylsulfanyl-2,3-dihy-
droquinazolin-4(1H)-one (5o): Yield: 1.19 g (70%), mp: 112–114 °C.
MS: m/z: 342 (M+, 1%). Calculated for C18H18N2O3S (342.41): C,
63.14; H, 5.30; N, 8.18. Found: C, 62.90; H, 5.48; N, 8.02. IR (KBr): ν
1690 (C]O) cm−1.1H NMR (500 MHz, CDCl3): δ = 3.40 (3H, s, OCH3),
3.50 (2H, t, J = 6.00 Hz, SCH 2), 3.70 (2H, q, J = 6.00 Hz, OCH2), 3.90
(3H, s, OCH3), 7.05 (2H, d, J = 9.00 Hz, H-2′, H-6′), 7.24 (2H, d,
J = 9.00 Hz, H-3′, H-5′), 7.41 (1H, t, J = 7.00 Hz, H-6), 7.63 (1H, d,
J = 7.50 Hz, H-8), 7.74 (1H, t, J = 7.00 Hz, H-7), 8.25 (1H, d,
J = 7.00 Hz, H-5). 13C NMR (500 MHz, CDCl3): δ = 31.92 (SCH 2),
58.71 (OCH3), 70.65 (OCH2), 114.95 (C-2′, C-6′), 119.90 (C-6), 125.76
(C-8), 126.20 (C-5), 127.30 (C-7), 128.30 (C-3′, C-5′), 130.26 (C-1′),
134.54 (C-4a), 147.79 (C-8a), 160.10 (C-2), 160.70 (C-4′), 162.10 (C-
4).
3-Phenyl-2-(2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyr-
anosylsulfanyl)-2,3-dihydroquinazol-in-4(1H)-one (8d): Yield:
2.67 g, mp: 122–124 °C (140–141 °C [38]). MS: m/z: 584.60 (M+, 2%).
Calculated for C28H28N2O10S (584.66): C, 57.53; H, 4.83; N, 4.79.
Found: C, 57.35; H, 5.01; N, 4.55. IR (KBr): ν 1745 (C]O), 1694 (C]O)
cm−1.1H NMR (500 MHz, CDCl3): δ = 1.97 (3H, s, Ac), 1.98 (3H, s, Ac),
2.00 (3H, s, Ac), 2.06 (3H, s, Ac), 3.90–4.60 (3H, m, H-5′, H-6′, H-6′),
3-Substituded
2-(2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyr-
anosylsulfanyl)-2,3-dihydroquin-azolin-4(1H)-ones (8a-j):
The nucleoside bases 4a-e (5 mmol) was suspended in anhydrous
9

A.I. Khodair, et al.
CarbohydrateResearch486(2019)107832
5.11 (2H, m, H-2′, 4′-H), 5.37 (1H, t, J = 9.00 Hz, 3′-H), 5.87 (1H, d, 2J
1’,2’ = 10.50 Hz, 1′-H), 7.28 (1H, t, J = 7.50 Hz, H-6), 7.42 (2H, d,
J = 7.50 Hz, H-2′, H-6′), 7.55 (1H, d, J = 7.50 Hz, H-8), 7.78 (4H, m, H-
3′, H-4′, H-5′, H-7), 8.26 (1H, d, J = 7.50 Hz, H-5). 13C NMR (500 MHz,
CDCl3): δ = 20.56 (4Ac), 61.97 (C-6′), 68.28 (C-2′), 68.87 (C-3′), 74.22
(C-4′), 76.42 (C-5′), 82.43 (C-1′), 120.20 (C-6), 126.45 (C-8), 127.39 (C-
5), 128.77 (C-7), 129.36 (C-4′), 129.77 (C-2′, C-6′), 129.88 (C-3′, C-5′),
130.41 (C-1′), 134.75 (C-4a), 147.43 (C-8a), 153.96 (C-2), 161.65 (C-
4), 169.14, 169.37, 170.11, 170.58 (4Ac).
(1H, dd, J = 5.50, 9.00 Hz, 4′-H), 4.85 (1H, dd, J = 3.00, 9.50 Hz, 2′-
H), 5.28 (3H, m, 3′-H, H-2allyl), 5.50 (2H, dt, J = 2.50, 10.50 Hz, H-
1
allyl), 5.90 (1H, d, 2J 1’,2’ = 11.00 Hz, 1′-H), 5.95 (2H, m, H-3allyl), 7.45
(1H, t, J = 7.00 Hz, H-6), 7.59 (1H, d, J = 8.00 Hz, H-8), 7.70(1H, t,
J = 7.00 Hz, H-7), 8.25 (1H, d, J = 8.00 Hz, H-5). 13C NMR (500 MHz,
CDCl3): δ = 20.61, 20.68 (4Ac), 46.31 (C-1allyl), 61.47 (C-6′), 66.24 (C-
2′), 67.38 (C-3′), 72.05 (C-4′), 75.15 (C-5′), 83.17 (C-1′), 118.96 (C-
3
allyl), 119.60 (C-6), 126.34 (C-8), 127.16 (C-5, C-7), 130.47 (C-2allyl),
134.55 (C-4a), 147.09 (C-8a), 153.07 (C-2), 161.38 (C-4), 169.72,
169.98, 170.23, 170.41 (4Ac).
3-(4-Methoxyphenyl)-2-(2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyr-
anosylsulfanyl)-2,3-dihy-droquinazolin-4(1H)-one (8e): Yield:
1.66 g (54%), mp: 152–154 °C. MS: m/z: 614 (M+, 1%). Calculated for
3-Phenyl-2-(2′,3′,4′,6′-tetra-O-acetyl-β-D-galactopyr-
anosylsulfanyl)-2,3-dihydroquinazo-lin-4(1H)-one
(8i):
Yield:
C
29H30N2O11S (614.62): C, 56.67; H, 4.92; N, 4.56. Found: C, 56.52; H,
2.30 g, mp: 131–133 °C (145–147 °C [38]). MS: m/z: 584.60 (M+, 2%).
Calculated for C28H28N2O10S (584.66): C, 57.53; H, 4.83; N, 4.79.
Found: C, 57.40; H, 5.12; N, 4.68. IR (KBr): ν 1749 (C]O), 1694 (C]O)
cm−1.1H NMR (500 MHz, CDCl3): δ = 1.98 (3H, s, Ac), 1.99 (3H, s, Ac),
2.01 (3H, s, Ac), 2.02 (3H, s, Ac), 4.16 (3H, m, H-5′, H-6′, H-6′), 5.20
(1H, dd, J = 3.25, 9.50 Hz, H-4′), 5.32 (1H, t, J = 10.50 Hz, 2′-H), 5.50
(1H, d, J = 10.50 Hz, 3′-H),5.90 (1H, d, 2J 1’,2’ = 10.50 Hz, 1′-H), 7.28
(1H, t, J = 7.50 Hz, H-6), 7.42 (2H, d, J = 7.50 Hz, H-2′, H-6′), 7.56
(1H, d, J = 8.00 Hz, H-8), 7.60 (4H, m, H-3′, H-4′, H-5′), 7.80 (1H, t,
J = 7.50 Hz, H-7), 8.40 (1H, d, J = 7.50 Hz, H-5). 13C NMR (500 MHz,
CDCl3): δ = 20.63 (4Ac), 61.43 (C-6′), 66.22 (C-2′), 67.36 (C-3′), 72.19
(C-4′), 75.05 (C-5′), 82.87 (C-1′), 124.90 (C-6), 126.48 (C-8), 127.38 (C-
5), 128.77 (C-7), 129.36 (C-4′), 129.81 (C-2′, C-6′), 129.89 (C-3′, C-5′),
130.42 (C-1′), 134.81 (C-4a), 147.59 (C-8a), 152.00 (C-2), 162.00 (C-
4), 169.10, 169.72, 170.42 (4Ac).
5.18; N, 4.39. IR (KBr): ν 1742 (C]O), 1699 (C]O) cm−1.1H NMR
(500 MHz, CDCl3): δ = 1.98 (3H, s, Ac), 1.99 (3H, s, Ac), 2.00 (3H, s,
Ac), 2.05 (3H, s, Ac), 3.88 (3H, s, OCH3), 3.96–4.26 (3H, m, H-5′, H-6′,
H-6′), 5.13 (2H, d, J = 9.00 Hz, H-2′, 4′-H), 5.36 (1H, t, J = 9.00 Hz, 3′-
H), 5.85 (1H, d, 2J 1’,2’ = 10.50 Hz, 1′-H), 7.02 (2H, d, J = 6.50 Hz, H-
3′, H-5′), 7.13 (1H, t, J = 7.50 Hz, H-6), 7.27 (1H, d, J = 7.50 Hz, H-8),
7.52 (2H, d, J = 6.50 Hz, H-2′, H-6′), 7.76 (4H, t, J = 7.50 Hz, H-7),
8.26 (1H, d, J = 7.50 Hz, H-5). 13C NMR (500 MHz, CDCl3): δ = 20.55
(4Ac), 61.98 (C-6′), 68.31 (C-2′), 68.89 (C-3′), 74.22 (C-4′), 76.41 (C-
5′), 82.43 (C-1′), 114.91 (C-3′, C-5′), 115.24 (C-6), 126.17 (C-8), 126.36
(C-5), 127.39 (C-7), 129.89 (C-2′, C-6′), 130.47 (C-1′), 134.67 (C-4a),
147.43 (C-8a), 154.62 (C-2), 160.70 (C-4′), 161.90 (C-4), 169.17,
169.37, 170.11, 170.56 (4Ac).
3-Methyl-2-(2′,3′,4′,6′-tetra-O-acetyl-β-D-galactopyr-
anosylsulfanyl)-2,3-dihydroquinaz-olin-4(1H)-ones (8f). Yield:
2.08 g (79%), mp: 159–161 °C. MS: m/z: 522 (M+, 0.4%). Calculated
for C23H26N2O10S (522.53): C, 52.87; H, 5.02; N, 5.36. Found: C, 52.50;
H, 5.16; N, 5.13. IR (KBr): ν 1746 (C]O), 1672 (C]O) cm−1.1H NMR
(500 MHz, CDCl3): δ = 1.91 (3H, s, Ac), 1.94 (3H, s, Ac), 1.98 (3H, s,
Ac), 2.02 (3H, s, Ac), 3.60 (3H, s, N3CH3), 4.10 (1H, m, H-6′), 4.23 (2H,
m, H-5′, H-6″), 5.28 (1H, dd, J = 3.25, 9.50 Hz, 4′-H), 5.50 (1H, t,
J = 10.00 Hz, 2′-H), 5.52 (1H, t, J = 9.00 Hz, 3′-H), 6.00 (1H, d, 2J
1’,2’ = 11.00 Hz, 1′-H), 7.40 (1H, t, J = 7.00 Hz, H-6), 7.58 (1H, d,
J = 8.00 Hz, H-8), 7.74(1H, t, J = 7.00 Hz, H-7), 8.25 (1H, d,
J = 8.00 Hz, H-5). 13C NMR (500 MHz, CDCl3): δ = 20.60, 20.68, 20.70
(4Ac), 30.42 (N3CH3), 61.55 (C-6′), 66.18 (C-2′), 67.41 (C-3′), 72.07 (C-
4′), 75.18 (C-5′), 82.75 (C-1′), 119.47 (C-6), 126.29 (C-5, C-8), 127.09
(C-7), 134.43 (C-4a), 147.07 (C-8a), 153.31 (C-2), 161.78 (C-4),
169.79, 169.96, 170.23, 170.42 (4Ac).
3-(4-Methoxyphenyl)-2-(2′,3′,4′,6′-tetra-O-acetyl-β-D-galacto-
pyranosylsulfanyl)-2,3-dih-ydroquinazolin-4(1H)-one (8j): Yield:
1.30 g (42%), mp: 124–126 °C. MS: m/z: 614 (M+, 0.5%). Calculated
for C29H30N2O11S (614.62): C, 56.67; H, 4.92; N, 4.56. Found: C, 56.48;
H, 5.20; N, 4.36. IR (KBr): ν 1742 (C]O), 1699 (C]O) cm−1.1H NMR
(500 MHz, CDCl3): δ = 1.92 (3H, s, Ac), 1.98 (3H, s, Ac), 2.00 (3H, s,
Ac), 2.10 (3H, s, Ac), 3.80 (3H, s, OCH3), 4.10 (3H, m, H-5′, H-6′, H-6′),
5.12 (1H, dd, J = 3.25, 9.50 Hz, 4′-H), 5.25 (1H, t, J = 10.50 Hz, 2′-H),
5.41 (1H, dd, J = 3.25, 9.50 Hz, 3′-H), 5.80 (1H, d, 2J 1’,2’ = 10.50 Hz,
1′-H), 6.94 (2H, d, J = 8.00 Hz, H-3′, H-5′), 7.05 (1H, t, J = 9.00 Hz, H-
6), 7.40 (1H, d, J = 8.00 Hz, H-8), 7.50 (2H, d, J = 9.00 Hz, H-2′, H-6′),
7.80 (4H, t, J = 7.50 Hz, H-7), 8.20 (1H, d, J = 8.00 Hz, H-5). 13C NMR
(500 MHz, CDCl3): δ = 20.66 (4Ac), 61.45 (C-6′), 66.24 (C-2′), 67.39
(C-3′), 72.23 (C-4′), 75.03 (C-5′), 82.87 (C-1′), 114.93 (C-3′, C-5′),
115.25 (C-6), 126.39 (C-8), 127.39 (C-5), 127.51 (C-7), 128.86 (C-2′, C-
6′), 130.92 (C-1′), 134.74 (C-4a), 147.80 (C-8a), 154.62 (C-2), 157.20
(C-4′), 161.90 (C-4), 167.00, 169.00, 170.20 (4Ac).
3-Ethyl-2-(2′,3′,4′,6′-tetra-O-acetyl-β-D-galactopyr-
anosylsulfanyl)-2,3-dihydroquinazol-in-4(1H)-one (8g). Yield:
2.35 g (87%), mp: 164–166 °C. MS: m/z: 536 (M+, 2%). Calculated for
3-Substituded
2-(β-D-glucopyranosylsulfanyl)-2,3-dihy-
C
24H28N2O10S (536.55): C, 53.72; H, 5.26; N, 5.22. Found: C, 53.58; H,
droquinazolin-4(1H)-ones (9a-h):
5.73; N, 5.00. IR (KBr): ν 1748 (C]O), 1666 (C]O) cm−1.1H NMR
(500 MHz, CDCl3): δ = 1.92 (3H, s, Ac), 2.00 (3H, s, Ac), 2.15 (3H, s,
Ac), 2.21 (3H, s, Ac), 1.37 (3H, t, J = 7.00 Hz, N3CH2CH3), 4.10 (1H, m,
H-6′), 4.22 (4H, m, N3CH2CH3, H-5′, H-6″), 5.27 (1H, dd, J = 3.25,
9.50 Hz, 4′-H), 5.50 (1H, t, J = 10.50 Hz, 2′-H), 5.54 (1H, t,
J = 9.00 Hz, 3′-H), 5.90 (1H, d, 2J 1’,2’ = 11.00 Hz, 1′-H), 7.44 (1H, t,
J = 7.00 Hz, H-6), 7.56 (1H, d, J = 8.00 Hz, H-8), 7.70 (1H, t,
J = 7.00 Hz, H-7), 8.24 (1H, d, J = 8.00 Hz, H-5). 13C NMR (500 MHz,
CDCl3): δ = 13.42 (N3CH2CH3), 20.61, 20.63, 20.70, 20.75 (4Ac),
39.89 (N3CH2CH3), 61.49 (C-6′), 66.24 (C-2′), 67.39 (C-3′), 72.07 (C-
4′), 75.14 (C-5′), 83.02 (C-1′), 119.76 (C-6), 126.28 (C-5, C-8), 127.01
(C-7), 134.40 (C-4a), 147.10 (C-8a), 152.73 (C-2), 161.40 (C-4),
169.80, 169.99, 170.25, 170.44 (4Ac).
The protected nucleosides 8a-e, g-i (1 mmol) was stirred in satu-
rated NH3/MeOH (5%, 50 mL) at room temperature for 12 h until the
starting material was consumed (TLC, ether petroleum ether, 90:10).
The solvent was removed in vacuo, and the residue was chromato-
graphed on silica gel with a gradient at 1–5% MeOH in CH2Cl2 to afford
the deprotected nucleosides 9a-h as a white solid.
3-Methyl-2-(β-D-glucopyranosylsulfanyl)-2,3-dihy-
droquinazolin-4(1H)-one (9a): Yield: 0.27 g (76%), mp: 186–188 °C.
MS: m/z: 354 (M+, 6%). Calculated for C15H18N2O6S (354.09): C,
50.84; H, 5.12; N, 7.90. Found: C, 50.48; H, 5.40; N, 7.56. IR (KBr): ν
3412 (OH), 1658 (C]O) cm−1.1H NMR (500 MHz, DMSO‑d6):
δ = 3.26–3.52(9H, m, H-2′, H-3′, H-4′, H-5′, H-6′, H-6″, N3CH3),4.42
(1H, t, J = 5.00 Hz, 6′-OH), 5.12 (1H, d, J = 5.00 Hz, 4′-OH), 5.20 (1H,
d, J = 3.60 Hz, 3′-OH), 5.50 (1H, d, 2J 1’,2’ = 12.00 Hz, 1′-H), 5.53 (1H,
d, J = 3.60 Hz, 2′-OH), 7.45 (1H, t, J = 7.00 Hz, H-6), 7.60 (1H, d,
J = 8.00 Hz, H-8), 7.77 (1H, t, J = 7.00 Hz, H-7), 8.15 (1H, d,
J = 7.00 Hz, H-5). 13C NMR (500 MHz, DMSO‑d6): δ = 30.69 (N3CH3)),
61.17 (C-6′), 70.13 (C-4′), 72.09 (C-2′), 79.06 (C-5′), 82.16 (C-3′), 85.50
(C-1′), 119.20 (C-6), 126.36 (C-8), 126.62 (C-5), 126.82 (C-7), 135.03
(C-4a), 147.29 (C-8a), 153.31 (C-2), 161.78 (C-4), 169.79, 169.96,
3-Allyl-2-(2′,3′,4′,6′-tetra-O-acetyl-β-D-galactopyr-
anosylsulfanyl)-2,3-dihydroquinazol-in-4(1H)-one (8h): Yield:
2.40 g (87%), mp: 146–148 °C. MS: m/z: 548 (M+, 30%). Calculated for
C
25H28N2O10S (548.56): C, 54.74; H, 5.14; N, 5.11. Found: C, 54.46; H,
5.18; N, 4.72. IR (KBr): ν 1745 (C]O), 1672 (C]O) cm−1.1H NMR
(500 MHz, CDCl3): δ = 1.93 (3H, s, Ac), 1.98 (3H, s, Ac), 2.10 (3H, s,
Ac), 2.20 (3H, s, Ac), 4.12 (1H, m, H-6′), 4.22 (2H, m, H-5′, H-6″), 4.67
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CarbohydrateResearch486(2019)107832
170.23, 170.42 (4Ac).
52.16; H, 5.47; N, 7.60. Found: C, 51.87; H, 5.68; N, 7.44. IR (KBr): ν
3404 (OH), 1664 (C]O) cm−1.1H NMR (500 MHz, CD3OD-d4):
δ = 1.39 (3H, t, J = 7.00 Hz, N3CH2CH3), 3.33 (2H, m, H-3′, H-4′), 3.66
(1H, m, H-5′), 3.73 (1H, t, J = 9.00 Hz, H-6′), 3.84 (1H, dd, J = 5.00,
9.00 Hz, H-6′), 4.00 (1H, dd, J = 2.50, 12.00 Hz, H-2′), 4.22 (1H, q,
J = 7.00 Hz, N3CH2CH3), 5.75 (1H, d, J = 10.50 Hz, H-1′), 7.45 (1H, t,
J = 7.00 Hz, H-6), 7.60 (1H, d, J = 8.00 Hz, H-8), 7.70 (1H, t,
J = 7.00 Hz, H-7), 8.15 (1H, d, J = 7.00 Hz, H-5). 13C NMR (500 MHz,
CD3OD-d4): δ = 13.59 (N3CH2CH3), 40.99 (N3CH2CH3)), 62.03(C-6′),
70.50(C-4′), 76.68(C-2′), 76.68(C-5′), 81.35(C-3′), 87.10(C-1′), 120.55
(C-6), 127.56 (C-5, C-8), 128.70 (C-7), 135.00 (C-4a), 148.80 (C-8a),
156.00(C-2), 163.20(C-4).
3-Ethyl-2-(β-D-glucopyranosylsulfanyl)-2,3-dihydroquinazolin-
4(1H)-one (9b): Yield: 0.29 g (79%), mp: 204–206 °C. MS: m/z: 368
(M+, 0.5%). Calculated for C16H20N2O6S (368.41): C, 52.16; H, 5.47; N,
7.60. Found: C, 51.93; H, 5.75; N, 7.48. IR (KBr): ν 3400 (OH), 1662
(C]O) cm−1.1H NMR (500 MHz, CD3OD-d4): δ = 1.38 (3H, t,
J = 7.00 Hz, N3CH2CH3), 3.33 (2H, m, H-3′, H-4′), 3.40 (1H, m, H-5′),
3.50 (1H, t, J = 9.00 Hz, H-6′), 3.71 (1H, dd, J = 5.00, 9.00 Hz, H-6′),
3.86 (1H, d, J = 12.00 Hz, H-2′), 4.23 (1H, q, J = 7.00 Hz, N3CH2CH3),
5.77 (1H, d, J = 10.00 Hz, H-1′), 7.45 (1H, t, J = 7.00 Hz, H-6), 7.60
(1H, d, J = 8.00 Hz, H-8), 7.70 (1H, t, J = 7.00 Hz, H-7), 8.15 (1H, d,
J = 7.00 Hz, H-5).13
C
NMR (500 MHz, CD3OD-d4): δ = 13.61
(N3CH2CH3), 40.02 (N3CH2CH3), 62.63 (C-6′), 71.25 (C-4′), 73.20 (C-
2′), 80.11 (C-5′), 82.72 (C-3′), 86.61 (C-1′), 116.13 (C-6), 120.55 (C-8),
127.21 (C-5), 127.49 (C-7), 135.79 (C-4a), 148.83 (C-8a), 155.81 (C-2),
163.23 (C-4).
3-Allyl-2-(β-D-galactopyranosylsulfanyl)-2,3-dihy-
droquinazolin-4(1H)-one (9g): Yield: 0.23 g (57%), mp: 184–185 °C.
MS: m/z: 380 (M+, 0.5%). Calculated for C17H20N2O6S (354.09): C,
53.67; H, 5.30; N, 7.36. Found: C, 53.52; H, 5.42; N, 7.21. IR (KBr): ν
3419 (OH), 1684 (C]O) cm−1.1H NMR (500 MHz, CD3OD-d4):
δ = 3.33 (2H, m, H-3′, H-4′), 3.65 (1H, m, H-5′), 3.74 (1H, dd, J = 3.50,
9.00 Hz, H-6′), 3.80 (1H, t, J = 9.00 Hz, H-6″), 3.99 (1H, dd, J = 5.00,
12.00 Hz, H-2′), 4.83 (2H, t, J = 1.75 Hz, H-1allyl),5.26 (2H, m, H-2allyl),
5.74 (1H, d, J = 10.50 Hz, H-1′), 5.92 (2H, m, H-3allyl),7.47 (1H, t,
J = 7.00 Hz, H-6), 7.62 (1H, d, J = 8.00 Hz, H-8), 7.79 (1H, t,
J = 6.50 Hz, H-7), 8.17 (1H, d, J = 7.00 Hz, H-5).13C NMR (500 MHz,
CD3OD-d4): δ = 47.49 (C-1allyl), 62.34 (C-6′), 70.52 (C-4′), 71.63 (C-2′),
76.67(C-5′), 81.34(C-3′), 87.29(C-1′), 118.75 (C-3allyl), 120.48 (C-6),
127.32 (C-8), 127.62 (C-5), 127.68 (C-7), 132.29 (C-2allyl), 135.93 (C-
4a), 148.82 (C-8a), 156.39 (C-2), 163.20 (C-4).
3-Allyl-2-(β-D-glucopyranosylsulfanyl)-2,3-dihydroquinazolin-
4(1H)-one (9c): Yield: 0.26 g (65%), mp: 92–94 °C. MS: m/z: 380 (M+
,
0.5%). Calculated for C17H20N2O6S (354.09): C, 53.67; H, 5.30; N, 7.36.
Found: C, 53.50; H, 5.45; N, 7.17. IR (KBr): ν 3412 (OH), 1686 (C]O)
cm−1.1H NMR (500 MHz, CD3OD-d4): δ = 3.33 (2H, m, H-3′, H-4′),
3.42 (1H, m, H-5′), 3.50 (1H, t, J = 9.00 Hz, H-6′), 3.68 (1H, dd,
J = 5.00, 12.00 Hz, H-6″), 3.84 (1H, dd, J = 1.50, 12.00 Hz, H-2′), 4.83
(2H, m, H-1allyl), 5.26 (2H, m, H-2allyl), 5.76 (1H, d, J = 9.50 Hz, H-1′),
5.90 (2H, m, H-3allyl), 7.47 (1H, t, J = 7.00 Hz, H-6), 7.62 (1H, d,
J = 8.00 Hz, H-8), 7.79 (1H, t, J = 6.50 Hz, H-7), 8.17 (1H, d,
J = 7.00 Hz, H-5).13C NMR (500 MHz, CD3OD-d4): δ = 47.50 (C-1allyl),
62.62 (C-6′), 71.23 (C-4′), 73.21 (C-2′), 80.10 (C-5′), 82.72 (C-3′), 86.77
(C-1′), 118.75 (C-3allyl), 120.48 (C-6), 127.32 (C-8), 127.62 (C-5),
127.68 (C-7), 132.29 (C-2allyl), 135.93 (C-4a), 148.84 (C-8a), 156.22
(C-2), 163.21 (C-4).
3-Phenyl-2-(β-D-galactopyranosylsulfanyl)-2,3-dihy-
droquinazolin-4(1H)-one (9h): Yield: 0.32 g (72%), mp: 154–156 °C.
MS: m/z: 416 (M+, 0.5%). Calculated for C20H20N2O6S (416.45): C,
57.68; H, 4.84; N, 6.73. Found: C, 57.48; H, 5.20; N, 6.49. IR (KBr): ν
3419 (OH), 1688 (C]O) cm−1.1H NMR (500 MHz, CD3OD): δ = 3.33
(2H, m, H-3′, H-4′), 3.59–3.74 (3H, m, H-5′, H-6′, H-6″), 3.96 (1H, dd,
J = 2.5, 12.00 Hz, H-2′), 5.63 (1H, d, 2J 1’,2’ = 10.00 Hz, 1′-H), 7.40
(2H, d, J = 3.00 Hz, H-2Ph, H-6Ph), 7.49 (1H, t, J = 7.50 Hz, H-6), 7.59
(3H, m, H-3Ph, H-4Ph, H-5Ph), 7.69 (1H, d, J = 8.00 Hz, H-8), 7.75 (1H,
d, J = 7.00 Hz, H-7), 8.16 (1H, d, J = 7.00 Hz, H-5). 13C NMR
(500 MHz, CD3OD): δ = 62.09 (C-6′), 70.47 (C-4′), 72.49 (C-2′), 81.20
(C-5′), 82.58 (C-3′), 86.67 (C-1′), 121.02 (C-6), 127.38 (C-8), 127.79 (C-
5), 127.86(C-4ph), 130.60 (C-2Ph, C-6ph), 130.65 (C-3Ph, C-5ph), 130.78
(C-1Ph), 136.42 (C-4a), 137.27, 149.29 (C-8a), 157.05 (C-2), 163.71 (C-
4).
3-Phenyl-2-(β-D-glucopyranosylsulfanyl)-2,3-dihy-
droquinazolin-4(1H)-one (9d): Yield: 0.35 g (84%), mp: 106–108 °C.
MS: m/z:416 (M+, 2%). Calculated for C20H20N2O6S (416.45): C, 57.68;
H, 4.84; N, 6.73. Found: C, 57.43; H, 5.02; N, 6.56. IR (KBr): ν 3421
(OH), 1686 (C]O) cm−1.1H NMR (500 MHz, CD3OD): δ = 3.18 (2H,
m, H-3′, H-4′), 3.20 (1H, d, J = 9.50 Hz, H-5′), 3.36 (1H,
dd,J = 8.75 Hz, H-6′), 3.66 (1H, dd, J = 5.50, 12.00 Hz, H-6″), 3.84
(1H, dd, J = 2.00, 14.50 Hz, H-2′), 5.50 (1H, d, 2J 1’,2’ = 10.50 Hz, 1′-
H), 7.28(2H, d, J = 3.00 Hz, H-2Ph, H-6Ph), 7.37 (1H, t, J = 7.50 Hz, H-
6), 7.47 (3H, m, H-3Ph, H-4Ph, H-5Ph), 7.57 (1H, d, J = 8.00 Hz, H-8),
7.71 (1H, d, J = 7.00 Hz, H-7), 8.06 (1H, d, J = 7.00 Hz, H-5). 13C NMR
(500 MHz, CD3OD): δ = 62.64 (C-6′), 71.23 (C-4′), 72.99 (C-2′), 80.07
(C-5′), 82.57 (C-3′), 86.18 (C-1′), 121.00 (C-6), 127.37 (C-8), 127.77 (C-
5), 127.83 (C-4ph), 130.58 (C-2Ph, C-6ph), 130.61 (C-3Ph, C-5ph), 130.78
(C-1Ph), 136.41 (C-4a), 137.21, 149.28 (C-8a), 156.86 (C-2), 163.70 (C-
4).
3.3. Molecular docking studies
All the molecular modeling studies were carried out on Intel® Core™
i3 CPU, 2.40 GHZ processor, and 3 GB memory with Windows 7 oper-
ating system using Molecular Operating Environment (MOE 2008-10
Chemical Computing Group, Canada) as the computational software.
For the docking studies, the crystal structure of Epidermal Growth
Factor Receptor tyrosine kinase (EGFR) with its co-crystallized ligand
(4-anilinoquinazolineerlo-tinib) was obtained from the freely accessible
Protein data bank (PDB code: 1M17) [48], verification process was
performed by re-docking of the co-crystallized ligand into the active site
using the default settings. S-glycosylated nucleosides derivatives were
constructed 2D using ChemBio-office 2015, converted to 3D by builder
interface of MOE program, and then were subjected to energy mini-
mization with MMFF94X force and the partial charges were auto-
matically calculated. Different conformers for each compound are im-
ported by systematic conformational of the MOE and saved in an
mdbdatabase file to be docked into the active site of the receptor. Each
complex was analyzed for interaction, 2D images were taken by using
the MOE visualizing tool.
3-(4-Methoxyphenyl)-2-(β-D-glucopyranosylsulfanyl)-2,3-dihy-
droquinazolin-4(1H)-one (9e): Yield: 0.286 g (62%), mp: 120–122 °C.
MS: m/z: 446 (M+, 0.5%). Calculated for C21H22N2O7S (446.47): C,
57.68; H, 4.84; N, 6.73. Found: C, 57.40; H, 5.08; N, 6.72. IR (KBr): ν
3450 (OH), 1682 (C]O) cm−1.1H NMR (500 MHz, CD3OD): δ = 3.32
(2H, m, H-3′, H-4′), 3.47 (1H, d, J = 9.50 Hz, H-5′), 3.66 (1H, dd,
J = 5.50, 12.00 Hz, H-6′), 3.66 (1H, dd, J = 5.50, 12.00 Hz, H-6″), 3.84
(1H, dd, J = 2.00, 14.50 Hz, H-2′), 3.90 (3H, s, OCH3), 5.60 (1H, d, 2J
1’,2’ = 10.50 Hz, 1′-H), 7.13 (2H, d, J = 6.50 Hz, H-3Ph, H-5Ph), 7.29
(1H, d, J = 8.00 Hz, H-3Ph, H-5Ph), 7.48 (3H, t, J = 7.50 Hz, H-6), 7.68
(1H, d, J = 8.00 Hz, H-8), 7.82 (1H, d, J = 7.00 Hz, H-7), 8.17 (1H, d,
J = 7.00 Hz, H-5). 13C NMR (500 MHz, CD3OD): δ = 56.15 (OCH3),
62.64 (C-6′), 71.24 (C-4′), 73.00 (C-2′), 80.08 (C-5′), 82.57 (C-3′), 86.16
(C-1′), 115.89 (C-3Ph, C-5ph), 115.96 (C-6), 120.98 (C-8), 127.78 (C-5),
129.47(C-2Ph, C-6ph), 131.69 (C-1Ph), 136.16 (C-4a), 149.31 (C-8a),
157.62 (C-4Ph), 162.44 (C-2), 163.98 (C-4).
3-Ethyl-2-(β-D-galactopyranosylsulfanyl)-2,3-dihy-
droquinazolin-4(1H)-one (9f): Yield: 0.22 g (57%), mp: 206–208 °C.
MS: m/z: 368 (M+, 0.4%). Calculated for C16H20N2O6S (368.41): C,
11

A.I. Khodair, et al.
CarbohydrateResearch486(2019)107832
3.4. In vitro cytotoxic activity
Acknowledgments
Cytotoxic efficacy of some derivatives against two cancer cell lines
including liver cancer (HepG-2), breast Michigan cancer foundation-7
(MCF-7), and normal human cell line (GMSC) using the MTT assay
[49]. Each cell line was propagated in a complete medium composed of
DMEM (High Glucose w/stable Glutamine w/Sodium Pyruvate, Bio-
west) or RPMI-1640 (Lonza Verviers SPRL, Belgium) supplemented
with 10% fetal bovine serum (Seralab, UK) and 1% Antibiotic (Anti-
biotic antimycotic, Biowest). The cells were incubated in 5% CO2 hu-
midified at 37 °C for growth according to the standard cell culture work
[50]. Cells were treated for 48 h with serial concentrations of com-
pounds (0.01, 0.1, 1, 10, 100 μM), and hence the percentages of cell
survival were determined using Graph Pad Prism 7.0. Values of IC50
were calculated using ORIGIN® 2018.
Research center (King Saud University) is thanked for carrying out
the measuring of IR, 1H NMR, 13C NMR and MS. Ahmed I. Khodair is
grateful for an Alexander von Humboldt-Fellowship.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.carres.2019.107832.
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Declaration of competing interest
[20] A.K. Tiwari, A.K. Mishra, A. Bajpai, P. Mishra, R.K. Sharma, V.K. Pandey,
There is no conflict of interest between the Authors.
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