Nucleosides 79: Synthesis, structure, and biological activity of new 6-arylidenamino-2-thio- and 2-benzylthiopyrimidine N-nucleosides

Article abstract of DOI:10.1080/15257770.2011.597628

The condensation of 6-amino-2-thioxo-2,3-dihydro-1H-pyrimidine-4-one [compound (1)] with aromatic aldehydes (2) afforded azomethine derivatives (3). The formed azomethines underwent glycosidation with α-acetobromoglucose (4) to form the corresponding pyri

Full text of DOI:10.1080/15257770.2011.597628

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Nucleosides 79: Synthesis, Structure,
and Biological Activity of New
6-Arylidenamino-2-Thio- and 2-
Benzylthiopyrimidine N-Nucleosides
Mosselhi A. N. Mosselhi a & Laila M. Break b
a Department of Chemistry, Faculty of Science, Taif University, Taif,
Saudi Arabia
b Department of Chemistry, Faculty of Science (Girls), Taif
University, Taif, Saudi Arabia
Published online: 08 Sep 2011.
To cite this article: Mosselhi A. N. Mosselhi & Laila M. Break (2011): Nucleosides 79: Synthesis,
Structure, and Biological Activity of New 6-Arylidenamino-2-Thio- and 2-Benzylthiopyrimidine N-
Nucleosides, Nucleosides, Nucleotides and Nucleic Acids, 30:9, 681-695
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Nucleosides, Nucleotides and Nucleic Acids, 30:681–695, 2011
Copyright ꢀC Taylor and Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770.2011.597628
NUCLEOSIDES 79: SYNTHESIS, STRUCTURE, AND BIOLOGICAL
ACTIVITY OF NEW 6-ARYLIDENAMINO-2-THIO- AND
2-BENZYLTHIOPYRIMIDINE N-NUCLEOSIDES
Mosselhi A. N. Mosselhi1 and Laila M. Break2
1Department of Chemistry, Faculty of Science, Taif University, Taif, Saudi Arabia
2Department of Chemistry, Faculty of Science (Girls), Taif University, Taif, Saudi Arabia
Graphical Abstract:
1) KOH/Acetone
O
N
AcO
O
N
2) MeONa/MeOH
OAc
N
X
CH
RS
O
(4)
Br
OAc
OAc
HO
N
O
OH
N
CH
X
N
H
RS
(7, 16)
OH
OAc
OBz
OH
BzO
BzO
(3, 13)
O
O
1) HMDS
N
(8)
R= H; CH2C6H5
2) MeONa/MeOH
CH
N
X
RS
N
O
HO
(11, 19)
OH
HO
The condensation of 6-amino-2-thioxo-2,3-dihydro-1H-pyrimidine-4-one [compound (1)] with
2
aromatic aldehydes (2) afforded azomethine derivatives (3). The formed azomethines underwent
glycosidation with α-acetobromoglucose (4) to form the corresponding pyrimidine N-glycosides
(6) and not S-glycosides (5). The interaction of (3) with 1-O-acetyl-2, 3, 5-tri-O-benzoyl-β-D-
ribofuranose (8) afforded the corresponding pyrimidine N-riboside (10) and not S-riboside (9).
Deacetylation and debenzoylation of each of (6) and (10) by using methanolic sodium methox-
ide afforded the corresponding free N-nucleosides (7) and (11), respectively. Next, the reaction of
2-benzylthio-6-benzylidenaminouracil (13) with (4) and (8) did not yield the corresponding pro-
tected N-nucleosides (14) and (17), whereas it afforded (15) and (18), respectively. The latter
compounds (15) and (18) were stirred in methanolic sodium methoxide to yield the corresponding
Received 15 September 2010; accepted 10 June 2011.
The authors thank the Taif University, Taif, Saudi Arabia, for the financial support for this project,
grant numbers 1-430-403 and 2-431-403.
Address correspondence to Mosselhi A. N. Mosselhi, Department of Chemistry, Faculty of Science,
Taif University, P. O. 888, Taif, Saudi Arabia. E-mail: mosselhi2008@hotmail.com
681

682
M. A. N. Mosselhi and L. M. Break
free N-nucleosides (16) and (19), respectively. The structures of products have been elucidated and
reported and also some of the products were screened for their antimicrobial activity.
Keywords
6-Arylidenaminothiopyrimidines; α-D-glucopyranosyl bromide; β-D-
ribofuranose; N -pyrimidine glycoside; N -pyrimidine nucleoside; antimicrobial activity
INTRODUCTION
Nucleosides are the most frequently used effective class of antiviral
agents, with over 20 drugs currently approved for the treatment of viral dis-
eases and a number of candidates in the clinical trials.[1a,1b,2] Consequently,
the intense search for new nucleoside derivatives attracted extensive atten-
tion. For example, Mackman synthesized a novel nucleoside phosphonate
that had anti-HIV activity.[3] Being bioactive molecules, pyrimidines are im-
portant components of the biological macromolecules, such as DNA and
RNA. Therefore, introducing the pyrimidines into nucleoside derivatives
may result in the discovery of a number of novel derivatives with potential
antitumor and antiviral activities. The explosion of new approaches for their
synthesis and, most importantly, their selective synthesis is an interesting
subject of organic and bioorganic chemistry.
Furthermore, 2-thiopyrimidine nucleosides are known to adopt referen-
tially a rigid C3ꢁ-endo sugar ring conformation; therefore, in RNA duplexes,
a modified s2U-A base pair is more stabilized than the unmodified one.[4–8]
Owing to the biological importance of pyrimidine nucleosides and as a
part of our continuing interest in the synthesis of new nucleosides[9,10–14]
as expected new potential antivirals, we have been encouraged to study a
synthetic strategy of new derivatives of thiopyrimidine N -nucleosides that
have not yet been reported in the literature.
RESULTS AND DISCUSSION
Condensation of equimolar quantities of 6-amino-2-thioxo-2,3-dihydro-
1H-pyrimidine-4-one [compound (1)] with aromatic aldehydes (2) in
dimethylformamide (DMF) in the presence of drops of acetic acid gave
the corresponding 6-arylidenamino-2-thioxo-2,3-dihydro-1H-pyrimidin-4-
ones (3) (see Scheme 1). The elucidation of the structures of (3) was based
on the spectral evidence (see Experimental section). Thus, the infrared (IR)
spectra of (3) revealed absorption bands for C S group at ν = 1175–1179
cm−1. The 1H NMR spectra showed characteristic signals for N CH proton
at δ = 7.80–7.95.
Reaction of the potassium salt of 6-arylidenamino-2-thioxo-2,3-dihydro-
1H-pyrimidin-4-ones (3) with 2,3,4,6-tetracetyl-O-acetyl-α-D-glucopyranosyl
bromide (4) in dry acetone did not give the S-glycosides (5); instead, it gave
the corresponding new N -glycosides (6) (see Scheme 1).

Nucleosides 7
683
O
O
H N
X
CHO
N
H
S
N
S
CH
X
N
H
NH2
N
H
(2)
(3)
(1)
AcO
OAc
O
O
BzO
BzO
OAc
(8)
(4)
Br
OAc
OBz
OAc
O
O
N
N
N
CH
AcO
X
N
H
S
N
CH
X
S
N
H
O
O
BzO
BzO
OAc
OAc
(5)
OBz
O
(9)
OAc
or
or
O
N
H
H N
S
AcO
N
S
CH
X
N
N
CH
X
N
O
O
BzO
BzO
(10)
OAc
OAc
OBz
(6)
OAc
CH3ONa/ CH3OH
CH3ONa/ CH3OH
O
O
H N
H N
S
S
N
CH
X
N
N
CH
X
N
HO
O
HO
HO
O
OH
OH
OH
OH
(11)
10, 11; X = H
(7)
2, 3, 6, 7; X = a, H; b, 4-CH3; c; 4-CH3O, d; 4-Cl
SCHEME 1
Thin layer chromatography (TLC) showed the formation of a single
unique compound in each case. The structure of the products (6) was estab-
lished and confirmed by elemental analyses and spectral data (IR, 1H NMR,
13C NMR; see Experimental section). IR spectra of (6) revealed absorption
bands for acetoxy carbonyl groups at ν = 1740–1750 cm−1. The 1H NMR spec-
trum of (6a) taken as a typical example of the prepared series showed the

684
M. A. N. Mosselhi and L. M. Break
anomeric proton as a doublet at δ = 6.35 with spin–spin coupling constant
of J 1 ,2 = 5.5 Hz corresponding to diaxial orientation of the H-1ꢁ and H-2ꢁ
protons[13]. The other six protons of the glucopyranosyl ring resonated at
δ = 3.95–6.35 region, whereas the four acetoxy groups appeared as four sin-
glets at δ = 2.20–2.25, in addition to the other expected signals for aromatic
and olefinic protons. However, 13C NMR spectrum of (6a) was characterized
by a signal of δ = 62.0–82.5 corresponding to the C’s atoms of the β-D-
glucopyranose, the four signals appearing at δ = 165.0–167.5 due to the four
acetoxy carbonyl carbon atoms, and the characteristic signal at δ = 173 due
to the presence of C S, the six signals at δ = 20.5–21.5 are attributed to the
acetate methyl carbon atoms. Another signal at δ = 158.5 corresponds to
N CH (see Experimental section).
ꢁ
ꢁ
Deacetylation of the blocked glycosides (6) was achieved in methanolic
sodium methoxide to afford the corresponding free N -nucleosides (7) (see
1
Scheme 1). The H NMR of (7) showed the expected base moiety protons
in addition to the sugar moiety protons (see Experimental section).
Next, the ribosylation of (3) (X H) with 1-O-acetyl-2,3,5-tri-O-benzoyl-
β-D-ribofuranose (8) was carried out by the silylation method according to
Vorbruggen[15] by refluxing of (3) in hexamethyl disilazane (HMDS) with
ammonium sulfate as a catalyst and then stirring of the silylated product with
ribose derivative (8) in dry acetonitrite and trimethylsilane [(TMS) triflate;
CF3SO2OSiMe3] at room temperature for 48 hours. This method yielded a
product in 65% of the benzoylated nucleosides (9) or (10) (see Scheme 1).
The structure of the latter product was established and confirmed on the
bases of its elemental analyses and spectral data (see Experimental section),
which were consistent with the structure of nucleoside (10) and not (9).
Thus, the analytical data for (10) revealed in its 1H NMR spectrum a doublet
at δ = 6.0 assigned to the anomeric proton of the ribose moiety with a
spin–spin coupling constant equal to 10 Hz that corresponds to a diaxial
orientation for the 1ꢁ- and 2ꢁ-H protons, i.e., the β-configuration.[9,10–14] 13
NMR spectrum of (10) revealed C S chemical shifts of δ 175.
C
Reaction of (10) with methanolic sodium methoxide at room tempera-
ture yielded the corresponding free N -nucleoside (11) (see Scheme 1). The
1H NMR of (11) showed the expected base moiety protons in addition to
the sugar moiety protons.
A distinction between the O-, N -, and S-nucleosides was possible by
1
comparison of the H NMR and 13C NMR spectra with those of litera-
ture data of similar compounds.[16] 13C S chemical shifts of δ 172.0 were
reported for cycloalkyl[4,5]-thieno[2,3-d]pyrimidin-4-one-2-thione, whereas
2-alkylthio-cycloalkyl[4,5]thieno[2,3-d]pyrimidin-4-one show chemical shifts
of C-2 ( C S ) around δ 159 ppm. For example, 13C NMR spectrum
of our nucleosides (6a) showed the characteristic signal at δ = 173
due to the presence of C S. This finding indicates the formation of
N -nucleosides.[16]

Nucleosides 7
685
The results of further investigation into the formation of N -nucleosides
showed that the reaction of 6-benzylideneamino-2-benzylthioxo-2,3-dihydro-
1H-pyrimidine-4-one (13), which is unreported in the literature and was ob-
tained by heating 6-amino-2-benzylthioxo-2,3-dihydro-1H-pyrimidine-4-one
(12) with benzaldehyde (2) in DMF and drops of acetic acid (see Scheme 2),
O
O
CHO
N
H
H
N
NH2
N
C6H5-CH2-S
N=CH
N
C6H5-CH2-S
(2)
(13)
(12)
AcO
OAc
O
O
BzO
OAc
(4)
Br
OAc
OBz
BzO
(8)
OAc
CH=N
AcO
S-CH2-C6H5
N
O
S-CH2-C6H5
N
N
CH=N
BzO
N
O
O
O
OAc
OAc
(14)
OAc
OBz
BzO
(17)
O
O
N
N
O
N
N=CH
C6H5-CH2-S
BzO
N=CH
C6H5-CH2-S
AcO
N
O
OAc
BzO
OBz
(15)
(18)
OAc
OAc
CH3ONa/ CH3OH
CH3ONa/ CH3OH
O
N
O
N
N
C6H5-CH2-S
C6H5-CH2-S
HO
N=CH
N=CH
N
O
HO
HO
O
OH
OH
(19)
OH
(16)
OH
SCHEME 2

686
M. A. N. Mosselhi and L. M. Break
with saugers (4) and (8), was achieved in a similar manner to yield the corre-
sponding protected N -nucleosides (15) and (18), respectively, and not the
products (14) and (17) (see Scheme 2). Compounds (15) and (18) were de-
protected in methanolic sodium methoxide to give the corresponding free
N -nucleosides (16) and (19), respectively (see Scheme 2). The structures of
products (15), (16), (18), and (19) are confirmed by spectral [methylsilane
(MS), IR, and 1H NMR] data (see Experimental section).
The formation of N -nucleoside (15) and not (14) is consistent with the
results reported by L. Strekowski.[17] He reported that the reaction of 6-aryl-
5-cyano-2-thiouracil (20) with α-acetobromoglucose (4) in ethanolic piperi-
dine afforded the corresponding N -glycoside (21) and did not give the N -
glycoside (22) (see Scheme 3).
O
CN
H
N
R
N
S
AcO
AcO
O
O
OAc
OAc
Br
OAc
O
OAc
OAc
CN
R
(4)
H
S
N
OAc
(21)
N
H
Piperidine/ EtOH
H
N
S
R
(20)
N
NC
AcO
O
O
OAc
OAc
OAc
(22)
SCHEME 3
1
The H NMR spectrum of (15) showed the anomeric proton of the
glucose moiety as a doublet at δ = 5.83 with a coupling constant J = 5.50 Hz
indicating β-configuration of the anomeric center.[13] The other protons of
the glucopyranose ring resonated at δ = 3.90–5.55, whereas the four acetoxy
groups appeared as four singlets at δ = 2.25–2.30. The 13C NMR revealed
the absence of a thione carbon atom at about δ = 173. The signals at δ
= 164.0–166.0 are due to the four acetoxy carbonyl carbon atoms and the

Nucleosides 7
687
signals at δ = 20.6–20.7 are assigned to the acetate methyl carbon atoms.
The five signals at δ = 62.5–81.5 were assigned to C-6ꢁ, C-4ꢁ, C-2ꢁ, C-3ꢁ, and
C-5ꢁ, respectively. The IR spectrum of compound (15) showed a signal at
1675 cm−1 for the C O group and stretching vibration frequencies of the
acetate carbonyl groups at 1745 cm−1.
1
However, the H NMR spectrum of (18) revealed an anomeric proton
signal around δ = 6.6 with a coupling constant value of 9.4 Hz consistent
with the reported data for other N -nucleosides.[9,10–14]
The 1H NMR of (16) and (19) showed the expected base moiety protons
in addition to the sugar moiety protons (see Experimental section).
ANTIMICROBIAL ACTIVITY
Eight products, (6a), (7a), (10), (11), (15), (16), (18), and (19), were
evaluated for their antibacterial and antifungal activities against two bacterial
species, namely, Escherichia coli (EC) and Staphylococcus aureus (SA), as well
as two fungal species, namely, Aspergillus fumigatus (AF) and Candida albicans
(CA).
The antibacterial and antifungal activities were carried out in the Mi-
crobiology Division of Microanalytical Center of Cairo University; using the
diffusion plate method,[18–20] a bottomless cylinder containing a measured
quantity (1 mL, mg/mL) of the sample is placed on an inhibition zone (9 cm
diameter) containing a solid bacterial medium (nutrient agar broth) or fun-
gal medium (Dox’s medium) that has been heavily seeded with the spore
suspension of the test organism. After incubation (24 hours for bacteria and
5 days for fungi), the diameter of the clear zone of inhibition surrounding
the sample is taken as a measure of the inhibitory power of the sample against
the particular test organism.
Most of the compounds were tested in vitro against gram-negative bac-
teria (EC anaerobic), gram-positive bacteria (SA), and antifungal activity
against CA and AF. The antibiotics ampicillin and tetracycline were used as
references to evaluate the potency of the tested compounds under the same
condition. The test results are depicted in Table 1 on the following basis:
The solvent used was dimethylsulfoxide and the concentration of the sample
was 100 µg/mL.
EXPERIMENTAL
All chemicals were supplied by Sigma-Aldrich and Merck (Germany).
IR spectra were recorded for KBr discs on Testscan Shimadzu FTIR 8000
1
Series and Bruker IFS 113V spectrophotometers (Germany); H NMR and
13C-spectra were recorded on a Varian Gemini 200 MHz NMR spectrometer
(Germany) by using TMS as an internal standard in CDCl3 and DMSO-d6 as
a solvent. TLC was performed on silica gel sheets F 1550 LS 254 of Schleicher

688
M. A. N. Mosselhi and L. M. Break
TABLE 1 Antibacterial and antifungal activities of the synthesized compounds’ inhibition zone
diameter (IZDa; mm/mg compound tested)
Fungi
Gram (−)
Gram (+)
Compound no.
EC
SA
AF
CA
Control: DMSO
Tetracycline antibacterial agent
0.0
28
0.0
26
0.0
—
0.0
—
+++
+++
Amphotericin B antifungal agent
—
—
16
++
0.0
−
15
++
0.0
−
(6a)
(7b)
(10)
(11)
(15)
(16)
(18)
(19)
10
+
10
+
13
13
0.0
−
12
++
++
++
0.0
−
15
14
0.0
−
++
12
++
12
0.0
−
13
++
++
++
0.0
−
13
11
0.0
−
++
11
++
12
0.0
−
14
++
++
++
13
12
0.0
−
13
++
14
++
++
12
++
++
14
++
0.0
−
Note: The test results revealed that all compounds exhibited moderate activity against the two bacte-
rial species and all compounds, except (6a) showed moderate activity against one fungal species, CA
(DMSO = dimethyl sulfoxide).
aIZD = 2–10 mm beyond control = + (low activity); IZD = 11–24 mm beyond control = ++ (moderate
activity); IZD = 25–35 mm beyond control = +++ (high activity).
& Schull and column chromatography on Merck silica gel 60 (particle size
0.063–0.20 mm). Melting points were measured on a Gallenkamp melting
point apparatus (UK) and are uncorrected. Elemental analyses were carried
out at the Microanalytical Centre (Cairo University, Egypt).
The starting materials, 6-amino-2-thioxo-2, 3-dihydro-1H-pyrimidine-
4-one (1),[21] and 6-amino-2-benzylthioxo-2,3-dihydro-1H-pyrimidine-4-on
(12),[22] were prepared as in the literature reported methods.
6-Arylidenamino-2-thioxo-2, 3-dihydro-1H-pyrimidin-4-ones (3)
and 6-Benzylidenamino-2-benzylthio-2, 3-dihydro-1H-
pyrimidin-4-ones (13)
General method: To a solution of 6-amino-2-thioxo-2, 3-dihydro-
1H-pyrimidine-4-one (1)[21] or 6-amino-2-benzylthioxo-2,3-dihydro-1H-
pyrimidine-4-one (12)[22] (1.43 g, 0.01 mol) in DMF (30 mL), an equivalent
amount of aromatic aldehyde (2) (0.01 mol) and few drops of acetic acid
were added. The reaction mixture was heated under reflux for 4 hours and
then left to cool. The solid product formed after pouring into ice/

Nucleosides 7
689
water was filtered and crystallized from the ethanol/dioxane mixture
to give 6-arylidenamino-2-thioxo-2,3-dihdro-1H-pyrimidin-4-ones (3) and
6-benzylidenamino-2-benzylthio-2,3-dihydro-1H-pyrimidin-4-ones (13), re-
spectively. Compounds (3a) and (3c) are reported in the literature.[23]
Compound (3b): Yield (75%); yellow crystals; mp 279◦C–280◦C; IR
(KBr cm−1): 3386 (NH), 1658 (C O), 1179 (C S); 1H NMR (DMSO-d6): δ
2.60 (s, 3H, CH3), 5.35 (s, 1H, H-5), 6.89 (d, 2H, Ar–H, J = 8.0 Hz), 6.95(d,
2H, Ar–H, J = 8.0 Hz), 7.95 (s, 1H, N CH), 11.30 (s, 1H, NH), 11.90 (s,
1H, NH); Anal. Calcd. for C12H11N3OS (245.2): C, 58.76; H, 4.52; N, 17.13;
S, 13.07. Found: C, 58.50%; H, 4.20%; N, 17.00%; S, 13.25%.
Compound (3d): Yield (63%); yellow crystals; mp 352◦C–354◦C; IR
1
(KBr cm−1): 3385 (NH), 1658 (C O), 1175 (C S); H NMR (DMSO-d6):
δ 5.34 (s, 1H, H-5), 6.99 (d, 2H, Ar–H, J = 8.0 Hz), 7.10 (d, 2H, Ar–H, J =
8.0 Hz), 7.90 (s, 1H, N CH), 11.42 (s, 1H, NH), 11.98 (s, 1H, NH); Anal.
Calcd. for C11H8N3ClOS (265.72): C, 49.72; H, 3.03; N, 15.81; S, 12.07.
Found: C, 55.10; H, 4.00; N, 16.22; S, 12.30%.
Compound (13): Yield (78%); yellow crystals; mp 233◦C–235◦C; IR (KBr
cm−1): 3375 (NH), 1665 (C O), 1H NMR (DMSO-d6): δ 4.45 (s, 2H, CH2),
5.50 (s, 1H, H-5), 7.20–7.50 (m, 10H, Ar–H), 7.90 (s, 1H, N CH), 11.50 (s,
1H, NH); Anal. Calcd. for C18H15N3OS (321.40): C, 67.27; H, 4.70; N, 13.07;
S, 9.98. Found: C, 67.10; H, 4.50; N, 13.08; S, 10.00%.
Synthesis of 6-Arylidenamino-1-(2ꢀ,3ꢀ,4ꢀ,6ꢀ-tetra-O-acetyl-β-D-
glucopyranosy)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-ones (6) and
6-Benzylidenamino-1-(2ꢀ,3ꢀ,4ꢀ,6ꢀ-tetra-O-acetyl-β-D-gluco-
pyranosy)-2-benzylthio-2,3-dihydro-1H-pyrimidin-4-ones (15)
General method: To a solution of (3) or (13) (5 mmol) in aqueous potas-
sium hydroxide [(0.28 g, 5 mmol) in distilled H2O (4 mL)] was added
a solution of 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (4) (2.06 g,
5 mmol) in acetone (20 mL). The reaction mixture was stirred at room
temperature overnight (12 hours) and judged to be complete by TLC
(CHCl3/MeOH 9:1). The solvent was evaporated under reduced pressure at
40◦C, and the crude product was filtered off and washed with distilled H2O
(3 × 4 mL) to remove potassium bromide formed. The product was dried
and crystallized from the proper solvent to afford the desired product (6) or
(15).
Compound (6a): Yield (65%), m.p. 220◦C–221◦C (Ethanol); IR (KBr) ν
1
cm−1: 1750, 1665, 1540, 1185; H NMR (DMSO-d6): δ 2.20–2.25 (4s, 12H,
4COCH3), 3.95 (m, 1H, H-5ꢁ), 4.15–4.30 (d, 2H, H-6ꢁ, J = 5.1 Hz), 4.95 (t,
1H, H-4ꢁ, J = 4.9 Hz), 5.20 (t, 1H, H-3ꢁ, J = 5.0 Hz), 5.35 (s, 1H, H-5), 5.50
(t, 1H, H-2ꢁ, J = 5.0 Hz), 6.35 (d, 1H, H-1ꢁ, J1 ,2 = 5.5 Hz), 6.95–7.15 (m, 5H,
Ar–H), 7.90 (s, 1H, N = CH), 11.42 (s, 1H, NH); 13C NMR (DMSO-d6): δ
ꢁ
ꢁ

690
M. A. N. Mosselhi and L. M. Break
20.5–21.5 (4 COCH3), (62.7, 75.5, 77.3, 80.8, 82.5) (glucose C’s), 95.0 (C5),
129.0, 130.0, 132.0, 134.0 (Ar–C’s), 158.5 (N CH), 159.8 (C6), 164.2 (C4),
165.0–167.5 (4 CO), 173.0 (C S); Anal. Calcd. for C25H27N3O10S (561.56):
C, 53.47; H, 4.85; N, 7.48; S, 5.71%.; Found: C, 53.22; H, 4.90; N, 7.40; S,
5.50%.
Compound (6b): Yield (72%), m.p. 225–227◦C (Ethanol); IR (KBr) ν
1
cm−1: 1743, 1670, 1515, 1175; H NMR (DMSO-d6): δ 2.10–2.16 (4s, 12H,
4COCH3), 2.50 (s, 3H, CH3), 3.95 (m, 1H, H-5ꢁ), 4.10–4.20 (d, 2H, H-6ꢁ, J =
5.1 Hz), 4.95 (t, 1H, H-4ꢁ, J = 4.85 Hz), 5.15 (t, 1H, H-3ꢁ, J = 5.0 Hz), 5.40
(s, 1H, H-5), 5.55 (t, 1H, H-2ꢁ, J = 5.0 Hz), 6.50 (d, 1H, H-1ꢁ, J1 ,2 = 5.4
Hz), 6.90 (d, 2H, Ar–H, J = 8.0 Hz), 7.00 (d, 2H, Ar–H, J = 8.0 Hz), 7.90
(s, 1H, N CH), 11.80 (s, 1H, NH); 13C NMR (DMSO-d6): δ 20.5–21.5 (4
COCH3), 25.5 (CH3), (62.5, 75.0, 77.3, 80.0, 81.5) (glucose C’s), 93.5 (C5),
129.8, 130.9, 135.2, 140.0 (Ar–C’s), 159.5 (N CH), 160.4 (C6), 163.8 (C4),
165.6–167.0 (4 CO), 173.2 (C S); Anal. Calcd. for C26H29N3O10S (575.59):
C, 54.25; H, 5.08; N, 7.30; S, 5.57%.; Found: C, 54.20; H, 4.95; N, 7.15; S,
5.60%.
ꢁ
ꢁ
Compound (6c): Yield (68%), m.p. 205◦C–206◦C (Ethanol); IR (KBr) ν
1
cm−1: 1740, 1669, 1520, 1182; H NMR (DMSO-d6): δ 2.12–2.20 (4s, 12H,
4COCH3), δ 3.75 (s, 3H, OCH3), 3.95 (m, 1H, H-5ꢁ), 4.15–4.25 (d, 2H, H-6ꢁ,
J = 5.1 Hz), 5.00 (t, 1H, H-4ꢁ J = 4.9 Hz), 5.10 (t, 1H, H-3ꢁ, J = 5.0 Hz),
5.35 (s, 1H, H-5), 5.45 (t, 1H, H-2ꢁ, J = 5.0 Hz), 6.35 (d, 1H, H-1ꢁ, J1 ,2
=
ꢁ
ꢁ
5.4 Hz), 6.95 (d, 2H, Ar–H, J = 8.0 Hz), 7.20 (d, 2H, Ar–H, J = 8.0 Hz),
7.89 (s, 1H, N CH), 11.65(s, 1H, NH); 13C NMR (DMSO-d6): δ 20.5–21.5 (4
COCH3), 55.1 (OCH3), (63.0, 74.5, 78.0, 80.5, 82.5) (glucose C’s), 92.8 (C5),
130.8, 132.9, 134.0, 157.8 (Ar–C’s), 160.1 (N CH), 161.5 (C6), 163.9 (C4),
164.8–167.5 (4 CO), 173.8 (C S); Anal. Calcd. for C26H29N3O11S (591.60):
C, 52.79; H, 4.94; N, 7.10; S, 5.42%.; Found: C, 53.00; H, 4.85; N, 7.15; S,
5.50%.
Compound (6d): Yield (55%), m.p. 212◦C–214◦C (Ethanol); IR (KBr)
1
ν cm−1: 1745, 1666, 1518, 1190; H NMR (DMSO-d6): δ 2.10–2.16 (4s,
12H, 4COCH3), 3.90 (m, 1H, H-5ꢁ), 4.10–4.22 (d, 2H, H-6ꢁ, J = 5.1
Hz), 4.98 (t, 1H, H-4ꢁ, J = 5.0 Hz), 5.15 (t, 1H, H-3ꢁ, J = 5.0 Hz),
5.40 (s, 1H, H-5), 5.50 (t, 1H, H-2ꢁ, J = 5.0 Hz), 6.40 (d, 1H, H-
1ꢁ, J1 ,2 = 5.5 Hz), 6.95 (d, 2H, Ar–H, J = 8.0 Hz), 7.25 (d, 2H,
Ar–H, J = 8.0 Hz), 7.85 (s, 1H, N CH), 11.50 (s, 1H, NH); 13C NMR (DMSO-
d6): δ 20.5–21.5 (4 COCH3), (62.5, 75.0, 77.5, 80.0, 81.5) (glucose C’s), 88.5
(C5), 130.8, 132.9, 134.0, 137.8 (Ar–C’s), 159.1 (N CH), 161.0 (C6), 163.0
(C4), 163.9–166.5 (4 CO), 172.9 (C S); Anal. Calcd. for C25H26ClN3O11S
(596.01): C, 50.38; H, 4.40; N, 7.05; S, 5.38%.; Found: C, 50.20; H, 4.45; N,
7.10; S, 5.30%.
ꢁ
ꢁ
Compound (15): Yield (69%), m.p. 125◦C–126◦C (Ethanol); IR (KBr)
ν cm−1: 1745, 1675, 1520 1180; 1H NMR (DMSO-d6): δ 2.25–2.30 (4s, 12H,

Nucleosides 7
691
4COCH3), 3.90 (m, 1H, H-5ꢁ), 4.15–4.25 (d, 2H, H-6ꢁ, J = 5.1 Hz), 4.45
(s, 2H, CH2), 4.95 (t, 1H, H-4ꢁ, J = 4.8 Hz), 5.20 (t, 1H, H-3ꢁ, J = 5.0
Hz), 5.35 (s, 1H, H-5), 5.55 (t, 1H, H-2ꢁ, J = 5.0 Hz), 5.83 (d, 1H, H-1ꢁ,
J1 ,2 = 5.50 Hz), 7.25–7.80 (m, 10H, Ar–H), 7.95 (s, 1H, N CH); 13C NMR
(DMSO-d6): δ 20.6–20.7 (4 CO CH3), 35.0 (CH2), (62.5, 75.0, 77.3, 80.0,
81.5) (glucose C’s), 89.5 (C5), 130.8, 132.9, 134.0, 137.8 (Ar–C’s), 159.0
(N CH), 161.5 (C6), 163.5 (C4), 164.0–166.0 (4 CO); Anal. Calcd. for
C32H33N3O10S (651.68): C, 58.98; H, 5.10; N, 6.45; S, 4.92%.; Found: C,
59.00; H, 5.25; N, 6.25; S, 4.90%.
ꢁ
ꢁ
Synthesis of 6-Arylidenamino-1-(2ꢀ,3ꢀ,4ꢀ,6ꢀ-tetra-hydroxy-β-
D-glucopyranosyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-ones (7)
and 6-Benzylidenmino-1-(2ꢀ,3ꢀ,4ꢀ,6ꢀ-tetra-hydroxy-β-D-gluco-
pyranosyl)-2-benzylthio-2,3-dihydro-1H-pyrimidin-4-ones (16)
General method: A mixture each of the protected nucleoside (6) or (15)
(2 mmol), absolute methanol (40 mL), and sodium methoxide (120 mg,
2.2 mol) was stirred at room temperature for 24 hours. Evaporation of the
solvent under vacuum gave a colorless solid, which was dissolved in hot water
and neutralized with acetic acid. The precipitate was filtered off and afforded
upon crystallization from water, the free nucleosides (7) or (16), respectively,
as colorless crystals or powder
Compound (7a): White powder, Yield (55%), m.p. 250◦C–251◦C; IR
1
(KBr) ν cm−1: 3450 (OH); H NMR (DMSO-d6): δ 1.50 (t, 2H, OH-2ꢁ +
OH-3ꢁ, J = 5.0 Hz), 1.85 (m, 2H, OH-4ꢁ+ OH-5ꢁ), 3.70 (s, 1H, H-2ꢁ), 4.10 (s,
2H, H-3ꢁ+ H-4ꢁ), 4.35 (d, 3H, H-5ꢁ+ H-6ꢁ, J = 5.2 Hz), 5.40 (s, 1H, H-5), 6.51
(t, 1H, H-1ꢁ, J1 ,2 = 5.0), 7.90 (s, 1H, N CH), 11.50 (s, 1H, NH); 13C NMR
(DMSO-d6): δ (71.0, 73.5, 77.5, 82.0, 84.5) (glucose C’s), 93.0 (C5), 128.9,
129.0, 131.0, 133.8 (Ar–C’s), 160.5 (N CH), 162.0 (C6), 166.2 (C4), 175.0
(C S); Anal. Calcd. for C17H19N3O6S (393.41): C, 51.90; H, 4.87; N, 10.68;
S, 8.15%.; Found: C, 51.95; H, 4.75; N, 10.50; S, 8.10%.
ꢁ
ꢁ
Compound (7b): Colorless crystals, Yield (67%), m.p. 235◦C–237◦C; IR
1
(KBr) ν cm−1: 3445 (OH); H NMR (DMSO-d6): δ 1.80 (t, 2H, OH-2ꢁ +
OH-3ꢁ, J = 5.0 Hz), 1.96 (m, 2H, OH-4ꢁ+ OH-5ꢁ), 2.60 (s, 3H, CH3), 3.79 (s,
1H, H-2ꢁ), 4.23 (s, 2H, H -3ꢁ+ H-4ꢁ), 4.45 (d, 3H, H-5ꢁ+ H-6ꢁ, J = 5.2 Hz),
5.50 (s, 1H, H-5), 6.55 (t, 1H, H-1ꢁ, J1 ,2 = 5.0), 7.00 (d, 2H, Ar–H, J = 8.0
Hz), 7.20 (d, 2H, Ar–H, J = 8.0 Hz), 7.95 (s, 1H, N CH), 11.43 (s, 1H,
NH); Anal. Calcd. for C18H21N3O6S (407.44): C, 53.06; H, 5.20; N, 10.31; S,
7.87%.; Found: C, 53.00; H, 5.05; N, 10.40; S, 7.80%.
ꢁ
ꢁ
Compound (7c): Colorless crystals, Yield (67%), m.p. 241◦C–242◦C; IR
(KBr) ν cm−1: 3450 (OH); 1H NMR (DMSO-d6): δ 1.78 (t, 2H, OH-2ꢁ + OH-3ꢁ,
J = 5.0 Hz), 1.95 (m, 2H, OH-4ꢁ+ OH-5ꢁ), 3.40 (s, 3H, OCH3), 3.80 (s, 1H,
H-2ꢁ), 4.25 (s, 2H, H-3ꢁ+ H-4ꢁ), 4.43 (d, 3H, H-5ꢁ+ H-6ꢁ, J = 5.2 Hz), 5.60

692
M. A. N. Mosselhi and L. M. Break
(s, 1H, H-5), 6.51 (t, 1H, H-1ꢁ, J1 ,2 = 5.0), 7.10 (d, 2H, Ar–H, J = 8.0 Hz),
7.25 (d, 2H, Ar–H, J = 8.0 Hz), 7.90 (s, 1H, N CH), 11.50 (s, 1H, NH);
Anal. Calcd. for C18H21N3O7S (423.44): C, 51.06; H, 5.00; N, 9.92; S, 7.57%.;
Found: C, 51.25; H, 5.10; N, 9.75; S, 7.55%.
ꢁ
ꢁ
Compound (7d): White powder, Yield (44%), m.p. 263◦C–264◦C; IR
1
(KBr) ν cm−1: 3448 (OH); H NMR (DMSO-d6): δ 1.65 (t, 2H, OH-2ꢁ +
OH-3ꢁ, J = 5.0 Hz), 1.80 (m, 2H, OH-4ꢁ+ OH-5ꢁ), 3.75 (s, 1H, H-2ꢁ), 4.15
(s, 2H, H-3ꢁ+ H-4ꢁ), 4.25 (d, 3H, H-5ꢁ+ H-6ꢁ, J = 5.2 Hz), 5.50 (s, 1H, H-5),
6.50 (t, 1H, H-1ꢁ, J1 ,2 = 5.0), 7.90 (s, 1H, N CH), 11.45 (s, 1H, NH); Anal.
Calcd. for C17H18ClN3O6S (427.86): C, 47.72; H, 4.24; N, 9.82; S, 7.49%.;
Found: C, 47.55; H, 4.45; N, 10.00; S, 7.55%.
ꢁ
ꢁ
Compound (16): White powder, Yield (42%), m.p. 240◦C–242◦C; IR
1
(KBr) ν cm−1: 3452 (OH); H NMR (DMSO-d6): δ 1.50 (t, 2H, OH-2ꢁ +
OH-3ꢁ, J = 5.0 Hz), 1.85 (m, 2H, OH-4ꢁ+ OH-5ꢁ), 3.70 (s, 1H, H-2ꢁ), 4.10 (s,
2H, H-3ꢁ+ H-4ꢁ), 4.35 (d, 3H, H-5ꢁ+ H-6ꢁ, J = 5.2 Hz), 5.40 (s, 1H, H-5), 6.45
(t, 1H, H-1ꢁ, J1 ,2 = 5.0), 7.20–7.70 (m, 10H, Ar–H), 7.90 (s, 1H, N CH);
Anal. Calcd. for C24H25N3O6S (483.54): C, 59.61; H, 5.21; N, 8.69; S, 6.63%.;
Found: C, 59.65; H, 5.15; N, 8.60; S, 6.50%.
ꢁ
ꢁ
Synthesis of 6-Benzylidenamino-1-(2ꢀ,3ꢀ,5ꢀ-tri-O-benzoyl-β-D-
ribofuranosyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (10) and
6-Benzylidenamino-2-benzylthioxo-1-(2ꢀ,3ꢀ,5ꢀ-tri-O-benzoyl-β-D-
ribofuranosyl)-2,3-dihydro-1H-pyrimidin-4-one (18)
General method: A mixture of (3) or (13) (10 mmol) and dry hexa-
methyldisilazane (50 mL) was heated under reflux for 10 hours with a
catalytic amount of ammonium sulfate (50 mg). After the clear solution
was cooled, it was evaporated to dryness under anhydrous condition to
give the silylated derivative, which directly was dissolved in 30 mL of dry
1, 2-dichloroethane. To this was added a solution of 1-O-acetyl-2, 3, 5-tri-O-
benzoyl-β-D-ribofuranose (8) (4.8 g, 9.8 mmol) in dry 1, 2-dichloroethane
(20 mL) was then added. The mixture was cooled in an ice bath and a solu-
tion of trimethylsilyl trifluoromethanesulfonate (2 mL, 10 mmol) in dry 1,
2-dichloroethane (10 mL) was added dropwise. It was stirred at room tem-
perature for 24 hours, then diluted with chloroform (300 mL), washed with
a saturated solution of aqueous sodium bicarbonate (100 mL), water (3 ×
50 mL), and dried over anhydrous sodium sulfate. The solvent was removed
in vacuo and the residue was chromatographed on silica gel with chloro-
form as the eluent to afford white solid that was crystallized from ethanol
to yield colorless crystals of the corresponding nucleoside derivative (10)
or (18).
Compound (10): Yield (70%), m.p. 160◦C–161◦C (Ethanol); IR (KBr) ν
cm−1: 1730, 1595, 1175; 1H NMR (CDCl3): δ 4.60–4.92 (m, 3H, 2 H-5ꢁ, H-4ꢁ),

Nucleosides 7
693
5.30 (s, 1H, H-5), 6.00 (d, 1H, H-1ꢁ, J1 ,2 = 10 Hz), 6.25–6.30 (pt, 1H, H-3ꢁ),
6.40–6.45 (pt, 1H, H-2ꢁ), 7.15–7.80 (m, 20H, Ar–H), 7.95 (s, 1H, N CH),
11.32 (s, 1H, NH); 13C NMR (CDCl3): 59, 71, 78, 84, 93, 121, 125–140,
151, 159, 168 (CO), 175 (C S); Anal. Calcd. for C37H29N3O8S (675.71):
C, 65.77; H, 4.33; N, 6.22; S, 4.75%.; Found: C, 65.59; H, 4.30; N, 6.10; S,
4.63%.
ꢁ
ꢁ
Compound (18): Yield (45%), m.p. 125◦C–126◦C (Ethanol); IR (KBr) ν
1
cm−1: 1734, 1600, 1180; H NMR (CDCl3): δ 4.45 (s, 2H, CH2), 4.66–4.95
(m, 3H, 2 H-5ꢁ, H-4ꢁ), 5.35 (s, 1H, H-5), 6.20–6.30 (pt, 1H, H-3ꢁ), 6.40–6.45
(pt, 1H, H-2ꢁ), 6.60 (d, 1H, H-1ꢁ, J1 ,2 = 9.4 Hz), 7.15–7.75 (m, 20H,
Ar–H), 7.95 (s, 1H, N CH); 13C NMR (CDCl3): 25, 60, 70, 78, 82, 92, 121,
125–140, 151, 159, 166–168 (CO); Anal. Calcd. for C44H35N3O8S (766.83):
C, 69.01; H, 4.61; N, 5.49; S, 4.19%.; Found: C, 69.00; H, 4.50; N, 5.33; S,
4.13%.
ꢁ
ꢁ
Synthesis of 6-Benzylidinamino-1-(β-D-ribofuranosyl)-2-thioxo-2,
3-dihydro-1H-pyrimidin-4-one (11) and 6-Benzylidinamino-2-
benzylthio-1-(β-D-ribofuranosyl)-2, 3-dihydro-1H-pyrimidin-4-one
(19)
General method: A mixture of the protected nucleoside (10) or (18)
(1 mmol), absolute methanol (20 mL), and sodium methoxide (60 mg,
1.1 mol) was stirred at room temperature for 24 hours. Evaporation of the
solvent under vacuum gave a colorless solid, which was dissolved in hot wa-
ter and neutralized with acetic acid. The precipitate was filtered off and
afforded upon crystallization from water to give the nucleosides (11) or (19)
as colorless crystals.
Compound (11): Yield (40%), m.p. 255◦C–256◦C; IR (KBr) ν cm−1: 3355
1
(OH); H NMR (DMSO-d6): δ 3.5–3.6 (m, 2H, 5ꢁ,5ꢁ-H); 3.9–4.0 (m, 1H,4ꢁ-
H); 4.15–4.2 (m, 1H, 3ꢁ-H); 4.35–4.45 (m, 1H, 2ꢁ-H); 4.7–4.8 (t, 1H, 5ꢁ-OH);
5.1–5.2 (d, 1H, 3ꢁ-OH); 5.30 (s, 1H, H-5); 5.4–5.5 (d, 1H, 2ꢁ-OH); 6.1–6.2
(d, 1H, J1 ,2 = 5.0 Hz, 1ꢁ-H); 7.10–7.75 (m, 5H, Ar–H), 7.90 (s, 1H, N CH),
11.50 (s, 1H, NH); Anal. Calcd. for C16H17N3O5S (363.39): C, 52.88; H, 4.72
N, 11.56; S, 8.82%.; Found: C, 52.70; H, 4.54; N, 11.50; S, 8.75%.
ꢁ
ꢁ
Compound (19): Yield (53%), m.p. 242◦C–243◦C; IR (KBr) ν cm−1: 3352
(OH), 1H NMR (DMSO-d6): δ 3.5–3.6 (m, 2H, 5ꢁ,5ꢁ-H); 3.8–3.9 (m, 1H,4ꢁ-
H); 4.10–4.15 (m, 1H, 3ꢁ-H); 4.25–4.35 (m, 1H, 2ꢁ-H); 4.45 (s, 2H, CH2);
4.65–4.75 (t, 1H, 5ꢁ-OH); 5.0–5.15 (d, 1H, 3ꢁ-OH); 5.25 (s, 1H, H-5); 5.35 (s,
ꢁ
1H, H-5); 5.40–5.50 (d, 1H, 2ꢁ-OH); 6.0 (d, 1H, J1 ,2 = 5.0 Hz, 1 -H); 7.15–7.80
(m, 10H, Ar–H), 7.95 (s, 1H, N = CH), 11.45 (s, 1H, NH); Anal. Calcd. for
C23H23N3O5S (453.51): C, 60.91; H, 5.11; N, 9.27; S, 7.07%.; Found: C, 60.90;
H, 5.00; N, 9.20; S, 6.88%.
ꢁ
ꢁ

694
M. A. N. Mosselhi and L. M. Break
ANTIMICROBIAL ASSAY
Cultures of two bacterial species, namely, EC and SA, as well as two fun-
gal species, namely, AF and CA, were used to investigate the antimicrobial
activity of the compounds’ eight products, (6a), (7a), (10), (11), (15), (16),
(18), and (19). The antimicrobial activity was assayed biologically by using
the diffusion plate technique. The latter technique was carried out by pour-
ing a spore suspension of the fungal species (1 cm3 of sterile water contains
approximately 108 conidia) or spreading bacterial suspension over a solidi-
fied malt agar medium. The layer is allowed to set for 30 minutes. A solution
of the test compounds (1.0 g = cm3) in DMF was placed onto sterile 5 mm
filter paper discs and allowed to dry; then the discs were placed on the center
of the malt agar plate and incubated at optimum incubation temperature
28◦C 2◦C. The fungicide Terbinfin and the bactericide chloramphenicol
were used as standards under the same conditions. Measurements were con-
sidered after 72 hours for fungi and 24 hours for bacteria. The results are
summarized in Table 1.
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