Synthesis and antimicrobial activity of some 2-pyridone nucleosides containing a sulfonamide moiety

Article abstract of DOI:10.1080/15257770.2013.775449

Glycosylation of 2-pyridonesulfonamide 1a,b with glycosyl/galactosyl bromide gave the corresponding glycosides 2a,b, 3a,b, 6a,b, and 7a,b, respectively. Deacetylation of the resulting glycosides gave the corresponding glycosides 4a,b, 5a,b, 8a,b, and 9a,b

Full text of DOI:10.1080/15257770.2013.775449

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Synthesis and Antimicrobial Activity of
Some 2-Pyridone Nucleosides Containing
a Sulfonamide Moiety
Ahmed H. Moustafa a , Hassan A. El-Sayed a , Abd El-Fattah Z. Haikal
a & Rasha A. Abd El-Hady a
a Department of Chemistry, Faculty of Science, Zagazig University,
Zagazig, Egypt
Published online: 14 Apr 2013.
To cite this article: Ahmed H. Moustafa , Hassan A. El-Sayed , Abd El-Fattah Z. Haikal & Rasha
A. Abd El-Hady (2013) Synthesis and Antimicrobial Activity of Some 2-Pyridone Nucleosides
Containing a Sulfonamide Moiety, Nucleosides, Nucleotides and Nucleic Acids, 32:5, 221-238, DOI:
10.1080/15257770.2013.775449
To link to this article: http://dx.doi.org/10.1080/15257770.2013.775449
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Nucleosides, Nucleotides and Nucleic Acids, 32:221–238, 2013
Copyright ꢀC Taylor and Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770.2013.775449
SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF SOME 2-PYRIDONE
NUCLEOSIDES CONTAINING A SULFONAMIDE MOIETY
Ahmed H. Moustafa, Hassan A. El-Sayed, Abd El-Fattah Z. Haikal,
and Rasha A. Abd El-Hady
Department of Chemistry, Faculty of Science, Zagazig University, Zagazig, Egypt
Glycosylation of 2-pyridonesulfonamide 1a,b with glycosyl/galactosyl bromide gave the corre-
2
sponding glycosides 2a,b, 3a,b, 6a,b, and 7a,b, respectively. Deacetylation of the resulting glycosides
gave the corresponding glycosides 4a,b, 5a,b, 8a,b, and 9a,b, respectively, in good yields. Further-
more, reaction of 2-pyridonesulfonamide 1b with lactosyl bromide gave a mixture the corresponding
N, O-lactosides 10 and 11, which were deacetylated to give the corresponding glycosides 12 and
13, respectively. The structures of the new synthesized compounds were characterized by using IR,
1H, 13C NMR spectra, and microanalysis. Selected members of these compounds were screened for
antimicrobial activity.
Keywords 2-Pyridonesulfonamide; glycosylation; lactosylation; antimicrobial activity
INTRODUCTION
The 2-pyridone structure has attracted considerable attention due to
its widespread occurrence in biologically important molecules (e.g., coen-
zyme of vitamin B6 family and in numerous alkaloids)[1–5] and in a number
of biologically active molecules.[1,2,6–11] For instance, pyridine-containing
compounds constitute an important class of anti-fibrosis drugs.[12–14] Fur-
thermore, the pyridone nucleus is associated with several biological activities
such as antimicrobial,[15] antiviral,[16] anticancer,[17] β−lactamase inhibitors
and anti−inflammatory,[18] and antimalarial agents. [19] On the other hand,
compounds containing sulfonamide moieties have shown a wide range of
biological activities,[20,21] such as antibacterial,[22,23] antimicrobial,[8,24,25] an-
titumor,[26] antiviral against HIV,[27] COX-2 selective inhibition,[28,29] anti-
convulsant, hypoglycemic, antihypertensive, histamine-H2-receptor antago-
nistic, and herbicidal activities.[30–32] Compounds combining the structural
features of pyridone and sulfonamide group into pyridonesulfonamide (PS)
Received 22 September 2012; accepted 8 February 2013.
Address correspondence to Hassan A. El-Sayed, Department of Chemistry, Faculty of Science,
Zagazig University, Zagazig, Egypt. E-mail: hasanneg@gmail.com
221

222
A. H. Moustafa et al.
Side chain SAR and
R
stereoelectronic effects
CN
O
N
H
HN
O
Metal - binding group
O
S
Hydrogen bond donor atom
Hydrogen bond acceptor atom
Group with affinity to enzyme hydrophobic subsite
H3C
FIGURE 1 Design of PS derivatives and structure–activity relationships.
have shown affinity toward metalloproteinases (Figure 1).[22] As a contin-
uation of our program for the search of biologically active pyridine-based
small molecules, herein, we wish to report on the synthesis and the biological
evaluations of glycosyalted pyridonesulfonamides 2–13.
RESULTS AND DISCUSSION
In order to gain more insights into the structure–activity relationship
of pyridonesulfonamides, we have manipulated the electronic effect on the
4-aryl moiety of the pyridone ring. The electronic effects are altered by the
varying electron-donating and electron-withdrawing substituents at the 4 and
6 positions of the pyridone ring.
The 2-pyridonesulfonamide derivatives 1a,b were synthesized according
to literature procedures[30,33,34] (Scheme 1). The IR spectra of 1a and 1b
displayed bands at 3225, 3231, 2217, 2218 and 1657, 1662 cm−1, indicating
the presence of NH, C≡N, and C O groups, respectively. Additionally,
1
the H NMR and 13C NMR are in agreement with the structures (see the
Experimental section).
The glycosylation of 1a,b with 2,3,4,6-tetra-O-acetyl-β-d-gluco or/galacto
pyranosyl bromide in anhydrous DMF/K2CO3 afforded a mixture of the
O-glycosyl derivatives (2a,b; 6a,b) and the N -glycosyl derivatives (3a,b;
7a,b), which were separated by silica gel chromatography, respectively
(Scheme 2).
The structures of the O- and N -glycosides derivatives were elucidated
from their analytical data, 1H and 13C NMR and IR. The IR spectra of 3a,b
and 7a,b showed the presence of bands at 1642, 1660, 1699, and 1685 cm−1,

Synthesis and Antimicrobial Activity of 2-Pyridone Nucleosides
223
H3C
O
H3C
O
Pyridine
+
ClO2S
CH3
NH
O2S
NH2
CH3
H3C
O
Ar1
O
CHO
NC
CN
O
OC2H5
+
Or
Amm. acetate
N
H
Ar
Ar
CHO
S
1a,b
Ar = p-CH3-C6H4-SO2NH-; Ar
1
a:
b:
=
p.(CH3)2CH-C6H4
Ar = p-CH3-C6H4-SO2NH-; Ar1 = thien-2-yl
Ar = p -CH3-C6H4-SO2NH-
SCHEME 1 Synthesis of 2-pyridonesulfonamide derivatives.
characterized the presence of amidic carbonyl groups, and assigned the
formation of N -glycosides, respectively, which disappeared with 2a,b and
6a,b. Thus, the β-configuration of compounds 2a,b, 3a,b, 6a,b, and 7a,b was
1
supported by their H and 13C NMR spectra, which revealed the anomeric
protons as doublets at δ = 6.21, 6.49, 6.20, 6.49, 6.57, 6.48, 6.35, and 6.42 ppm
with coupling constants of J = 8.10–8.40 Hz, respectively. The anomeric
carbons were seen at δ = 93.79, 93.83, 91.25, 91.23, 93.90, and 89.91 ppm,
respectively, which distinguished the formation of O- and N -glycosides.
The deacetylation of O- and N -glycoside derivatives 2a,b, 3a,b, 6a,b, and
7a,b in the presence of TEA/MeOH and few drops of water[35,36] led to the
formation of the free glycosides 4a,b, 5a,b, 8a,b, and 9a,b, respectively, in
high yield (Scheme 2). The IR spectra of the resulting compounds exhibited
1
broadbands at 3379–3432 cm−1 attributed to the hydroxyl groups. The H
NMR spectra and elemental analysis of the deacetylated compounds also
confirmed the structures of the compounds.
Additionally, the reaction of N -(4-(5-cyano-6-oxo-4-(4-thien-2-yl)-1,6-dihy
dropyridin-2-yl)phenyl)-4-methylbenzensulfonamide (1b) with 2,3–6-tri-O-
acetyl-4-O-(2,3,4,6-tetra-O-acetyl-β - d-galactopyranosyl) -α- d-gluco-pyranosyl
bromide gave the corresponding O- and N -lactoside derivatives 10 and 11,
respectively.

224
A. H. Moustafa et al.
Ar1
Ar1
N
CN
O
CN
O
K2CO3
DMF
Ar
N
H
Ar
1a,b
K
R' OAc
O
R
AcO
AcO
Br
Ar1
N
Ar1
CN
CN
O
Ar
OAc
O
R'
Ar
R'
N
+
O
OAc
R
O
AcO
AcO
R
AcO
3a,b
7a,b
AcO
2a,b
6a,b
MeOH
Et3N
MeOH
Et3N
Ar1
N
Ar1
CN
O
CN
O
Ar
Ar
R'
N
R'
OH
OH
O
R
O
HO
R
HO
HO
HO
5a,b
9a,b
4a,b
8a,b
Comp. No.
1a
1b
Ar
Ar1
R
R′
p.CH3-C6H4-SO2-NH-C6H4
p.CH3-C6H4-SO2-NH-C6H4
p.CH3-C6H4-SO2-NH-C6H4
p.CH3-C6H4-SO2-NH-C6H4
p.CH3-C6H4-SO2-NH-C6H4
p.CH3-C6H4-SO2-NH-C6H4
p.CH3-C6H4-SO2-NH-C6H4
p.CH3-C6H4-SO2-NH-C6H4
p.CH3-C6H4-SO2-NH-C6H4
p.CH3-C6H4-SO2-NH-C6H4
p.(CH3)2CH-C6H4
Thien-2-yl
p.(CH3)2CH-C6H4
Thien-2-yl
p.(CH3)2CH-C6H4
Thien-2-yl
p.(CH3)2CH-C6H4
Thien-2-yl
p.(CH3)2CH-C6H4
Thien-2-yl
2a, 3a
2b, 3b
6a, 7a
6b, 7b
4a, 5a
4b, 5b
8a, 9a
8b, 9b
OAc
OAc
H
H
H
OAc
OAc
H
H
OH
OH
H
OH
OH
H
H
SCHEME 2 Glycosylation of 2-pyridonesulfonamide derivatives.

Synthesis and Antimicrobial Activity of 2-Pyridone Nucleosides
225
Ar1
CN
O
OAc
AcO
AcO
OAc
AcO
O
+
O
O
Ar
N
H
AcO
OAc
Br
1b
Ar1
N
Ar1
N
CN
O
CN
O
Ar
Ar
OAc
AcO
AcO
OAc
OAc
AcO
AcO
OAc
O
O
+
O
O
O
O
AcO
OAc
AcO
OAc
OAc
OAc
11
10
MeOH
MeOH
Et3N
Et3N
Ar1
Ar1
CN
O
CN
O
Ar
OH
N
Ar
N
OH
OH
HO
OH
HO
O
O
O
O
O
HO
HO
O
OH
HO
OH
HO
OH
OH
Ar = p-CH3-C6H4-SO2NH-C6H4; Ar1 = Thien-2-yl
13
12
SCHEME 3 Lactosylation of 2-pyridonesulfonamide derivatives.
Deacetylation of lactosides derivatives 10 and 11 under the previous
conditions gave the corresponding deprotected lactosides 12 and 13, re-
spectively (Scheme 3). The IR spectrum of 10 displayed bands at 2219 and
1747 cm−1 for the C≡N and acetoxy carbonyl groups, respectively, with
the absence of the amide carbonyl group, which indicates the formation
of the O-lactoside. In compound 11, the presence of a band at 1642 cm−1
assigned the formation of N -lactoside, which was separated by silica gel chro-
1
matography. The H NMR spectrum of compound 10 exhibited signals at
δ = 1.90–2.11 ppm for seven acetoxy methyl groups and a doublet at δ =
6.65 ppm that was characteristic for the anomeric proton with J = 8.72 Hz,

226
A. H. Moustafa et al.
thus confirming the diaxial orientation (β-configuration) of compound 10.
Its 13C NMR spectrum showed the anomeric carbon at δ = 89.0 ppm. The IR
spectra of the deprotected lactosides 12 and 13 revealed the absence of ace-
toxy carbonyl groups and the presence of OH groups as broadbands at 3385
and 3391 cm−1, respectively. Also, the structure of compounds confirmed
1
by its H NMR results, as well as elemental analysis (see the Experimental
section).
CONCLUSION
In summary, we have described the synthesis of some O- and N -
glycosides derivatives by alkylation of 2-pyridonesulfonamide with glucosyl
or/galactosyl and lactosyl bromide. Some of the synthesized compounds
were screened for antimicrobial activity, which showed that compounds 4b,
5a, 7b, 8a, 9a, and 12 have significant antibacterial activity and compounds
2a, 3b, 6a, and 10 have higher activity, while all the tested compounds have
a significant antifungal activity compared with the standard drugs.
EXPERIMENTAL
All melting points are uncorrected and were measured using an Elec-
tro thermal IA 9100 apparatus. Thin layer chromatography (TLC) was per-
formed on Merck Silica Gel 60F254 with detection by ultraviolet light (UV)
and by the charring with 10% EtOH solution of H2SO4. The IR spectra
(KBr discs) were recorded on a Pye Unicam Sp-3–300 or a Shimadzu FTIR
8101 PC infrared spectrophotometer (Cairo University, Cairo, Egypt). The
operation frequency was 300 MHz for 1H and 75.5 MHz for 13C NMR using
JOEL-JNM-LA 300 MHz spectrometer. The coupling constants (J ) are given
in Hertz. The chemical shifts are expressed on the δ (ppm) scale using TMS
as the standard reference. The antimicrobial activities were carried in the
Microbiology Department, Faculty of Pharmacy, Zagazig University. Elemen-
tal analyses were determined on a Perkin Elmer 240 (Microanalysis Center,
Konstanz University, Germany).
N-(4-Acetylphenyl)-4-Methylbenzensulfonamide
A mixture of p-aminoacetophenone (10 mmol) and toluenesulfonyl
chloride (10 mmol) in pyridine (10 mL) was heated under reflux for 2 hours.
After cooling, the reaction mixture was poured into ice water, the formed
product filtered off, washed with water, and recrystallized from ethanol.
Yield: 93%, mp: 218–220◦C. IR (KBr): 3219 cm−1 (NH), and 1666 cm−1
(C O, acetyl). 1H NMR (DMSO-d6): δ = 2.28 (s, 3H, CH3), 3.33 (s, 3H,
CH3CO), 7.18 (d, 2H, J = 8.40 Hz, Ar H), 7.35 (d, 2H, J = 7.50 Hz,
Ar H), 7.70 (d, 2H, J = 8.40 Hz, Ar H), 7.80 (d, 2H, J = 7.50 Hz, Ar H),

Synthesis and Antimicrobial Activity of 2-Pyridone Nucleosides
227
10.76 (s, 1H, NH). Anal. calcd for C15H15NO3S (289.35): C, 62.26; H, 5.23;
N, 4.84. Found: C, 62.23; H, 5.24; N, 4.85.
General Procedure for Synthesis of Heterocyclic Bases (1a,b)
A mixture of N -(4-acetylphenyl)-4-methylbenzensulfonamide (10 m
mol), ethyl cyanoacetate (10 mmol), appropriate aldehyde (10 mmol), and
ammonium acetate (80 mmol) in ethanol (20 mL) was heated under reflux
for 5 hours, according to the literature,[33] the formed product was filtered
off and recrystallized from acetic acid.
General Procedure for Synthesis of Nucleosides
A solution of 2,3,4,6-tetra-β-d-gluco, galacto, and lactopyranosyl bromide
(10 mmol) in dry DMF (10 mL) was added to a solution of compound
1a,b (10 mmol) in dry DMF (10 mL) in the presence of anhydrous K2CO3
(11 mmol), the reaction mixture was stirred at room temperature and fol-
lowed by TLC. The solvent was removed under reduced pressure, the residue
was washed with distilled water to remove the inorganic residue, and then the
formed solid product was separated by silica gel chromatography (200–400
mesh) using CH2Cl2/MeOH (9.9:0.1) as eluent.
General Procedure for Deacetylation
A mixture of nucleosides (10 mmol) in methanol (20 mL), triethylamine
(1 mL) and few drops of water was stirred overnight at room tempera-
ture,[35,36] and then the solvent was removed under reduced pressure. The
residue was crystallized from methanol.
N-(4-(5-Cyano-4-(4-isopropylphenyl)-6-oxo-1,6-dihydropyridin-2-yl)phe-
ny)-4-methylbenzensulfonamide (1a). Yield: 60%, as yellow crystals, mp:
320–321◦C. IR (KBr): 3225 cm−1 (NH), 2217 cm−1 (C≡N), and 1657 cm−1
(C O, amide). 1H NMR (DMSO-d6): δ = 1.25 (d, 6H, J = 6.9 Hz,
(CH3)2CH), 2.33 (s, 3H, CH3), 2.96 (m, 1H, CH(CH3)2), 6.78 (s, 1H,
pyridone-H-5), 7.22 (d, 2H, J = 8.70 Hz, Ar H), 7.35 (d, 2H, J = 8.40 Hz,
Ar H), 7.41 (d, 2H, J = 8.40 Hz, Ar H), 7.62 (d, 2H, J = 8.10 Hz, Ar H),
7.73 (d, 2H, J = 8.10 Hz, Ar H), 7.79 (d, 2H, J = 8.70 Hz, Ar H), 10.65
(s, 1H, NH), 12.91 (s, 1H, NH). Anal. calcd for C28H25N3O3S (483.58): C,
69.54; H, 5.21; N, 8.69. Found: C, 69.56; H, 5.22; N, 8.68.
N-(4-(5-Cyano-6-oxo-4-(4-thien-2-yl)-1,6-dihydropyridin-2-yl)phenyl)-4-
methylbenzensulfonamide (1b). Yield: 63%, as yellow crystals, mp:
315–317◦C. IR (KBr): 3231 cm−1 (NH), 2218 cm−1 (C≡N), and 1662 cm−1
1
(C O, amide). H NMR (DMSO-d6): δ = 2.20 (s, 3H, CH3), 6.71 (s, 1H,
pyridone-H-5), 7.07–7.65 (m, 10H, Ar H), 7.85 (t, 1H, J = 4.50, 4.23 Hz,
thiophene-H), 10.93 (s, 1H, NH), 12.32 (s, 1H, NH). 13C NMR (DMSO-d6):
δ = 21.4 (CH3), 104.2, 115.5 (C≡N), 118.9, 127.2, 128.1, 129.0, 129.4, 130.3,

228
A. H. Moustafa et al.
131.1, 132.2, 132.7, 135.6, 137.0, 137.2, 141.1, 144.1, 151.1, and 162.6 (Ar-C
and C O). Anal. calcd for C23H17N3O3S2 (447.53): C, 61.73; H, 3.83; N,
9.39. Found: C, 61.71; H, 3.82; N, 9.40.
N-(4-(5-Cyano-4-(isopropylphenyl)-6-(2ꢁ,3ꢁ,4ꢁ,6ꢁ-tetra-O-acetyl-β-D-glu
copyranosyloxy)-1,6-dihydropyridin-2-yl)phenyl)-4-methylbenzenesulfona
mide (2a). Yield: 60%, as colorless crystals, mp: 107–109◦C. IR (KBr):
3256 cm−1 (NH), 2223 cm−1 (C≡N), and 1755 cm−1 (C O, acetoxy).
1H NMR (DMSO-d6): δ = 1.10 (d, 6H, J = 6.9 Hz ((CH3)2CH)), 1.85,
1.96, 1.99, and 2.03 (4s, 12H, 4 CH3CO), 2.36 (s, 3H, CH3), 2.84 (m, 1H,
CH(CH3)2), 4.15 (dd, 1H, J 5 ,6 = 4.45, J 6 ,6 = 11.72 Hz, H-6ꢁ), 4.25 (dd,
ꢁ
ꢁ
ꢁ
ꢁꢁ
1H, J 5 ,6 = 4.96, J 6 ,6 = 11.72 Hz, H-6ꢁꢁ), 4.91 (m, 1H, H-5ꢁ), 5.07 (t, 1H, J
ꢁ
ꢁ
ꢁ
ꢁꢁ
= 9.23 Hz, H-4ꢁ), 5.27 (t, 1H, J 1 ,2 = 8.15, J 2 ,3 = 9.58 Hz, H-2ꢁ), 5.49 (dd,
ꢁ
ꢁ
ꢁ
ꢁ
1H, J 2 ,3 = 9.58, J 3 ,4 = 9.23 Hz, H-3ꢁ), 6.21 (d, 1H, J 1 ,2 = 8.15 Hz, H-1ꢁ),
6.71 (s, 1H, pyridone-H-5), 7.12 (d, 2H, J = 8.43 Hz, Ar H), 7.22 (d, 2H,
J = 8.32 Hz, Ar H), 7.53 (d, 2H, J = 8.32 Hz, Ar H), 7.71 (d, 2H, J =
8.17 Hz, Ar H), 7.87 (d, 2H, J = 8.17 Hz, Ar H), 8.13 (d, 2H, J = 8.42 Hz,
Ar H), 10.56 (s, 1H, NH). 13C NMR (DMSO-d6): δ = 15.8 ((CH3)2CH),
20.08, 20.11, 20.15, and 20.20 (4 CH3CO), 20.32 (CH3), 30.4 (CH(CH3)2),
63.25 (C-6ꢁ), 65.7 (C-4ꢁ), 66.73 (C-3ꢁ), 68.7 (C-2ꢁ), 70.48 (C-5ꢁ), 93.79 (C-1ꢁ),
115.0 (C≡N), 119.3, 127.3, 128.2, 128.6, 129.1, 129.3, 130.2, 131.4, 133.6,
136.9, 137.0, 139.5, 141.0, 152.1, 158.0, 158.6, 162.1, (Ar-C and C N), 168.0,
169.3, 170.0, and 171.2 (4 C O). Anal. calcd for C42H43N3O12S (813.87):
C, 61.98; H, 5.33; N, 5.16. Found: C, 62.01; H, 5.32; N, 5.19.
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
N-(4-(5-Cyano-6-(2ꢁ,3ꢁ,4ꢁ,6ꢁ-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-
(thien-2-yl)-1,6-dihydropyridin-2-yl)phenyl)-4-methylbenzenesulfonamide
(2b). Yield: 63%, as colorless crystals, mp: 101–103◦C. IR (KBr): 3274 cm−1
1
(NH), 2226 cm−1 (C≡N), and 1735 cm−1 (C O, acetoxy). H NMR
(DMSO-d6): δ = 1.96, 1.98, 2.01, and 2.05 (4s, 12H, 4 CH3CO), 2.20 (s, 3H,
CH3), 3.98 (dd, 1H, J 5 ,6 = 4.78, J 6 ,6 = 11.53 Hz, H-6ꢁ), 4.31 (dd, 1H, J 5 ,6
ꢁ
ꢁ
ꢁ
ꢁꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁꢁ
ꢁꢁ
= 5.06, J 6 ,6 = 11.53 Hz, H-6 ), 5.0 (m, 1H, H-5 ), 5.28 (t, 1H, J = 9.42 Hz,
H-4ꢁ), 5.47 (t, 1H, J 1 ,2 = 8.23, J 2 ,3 = 9.12 Hz, H-2ꢁ), 5.83 (dd, 1H, J 2 ,3
=
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
9.12, J 3 ,4 = 9.41 Hz, H-3ꢁ), 6.49 (d, 1H, J 1 ,2 = 8.23 Hz, H-1ꢁ), 6.89 (s, 1H,
pyridone-H-5), 7.15–7.83 (m, 10H, Ar H), 8.11 (dd, 1H, J = 4.24, 3.85 Hz,
thiophene-H), 10.57 (s, 1H, NH). 13C NMR (DMSO-d6): δ = 20.34, 20.72,
21.01, and 21.40 (4 CH3CO), 21.64 (CH3), 69.66 (C-6ꢁ), 70.47 (C-4ꢁ), 71.83
(C-3ꢁ), 72.04 (C-2ꢁ), 72.46 (C-5ꢁ), 93.83 (C-1ꢁ), 113.4, 115.0 (C≡N), 119.3,
127.1, 128.2, 128.7, 129.0, 129.3, 130.3, 131.0, 133.6, 137.0, 139.5, 141.0,
144.0, 148.7, 156.8, 162.6 (Ar-C and C N), 169.3, 169.8, 170.0, and 170.3,
(4 C O). Anal. calcd for C37H35N3O12S2 (777.82): C, 57.13; H, 4.54; N,
5.40. Found: C, 57.11; H, 4.57; N, 5.38.
ꢁ
ꢁ
ꢁ
ꢁ
N-(4-(5-Cyano-4-(isopropylphenyl)-6-oxo-1-(2ꢁ,3ꢁ,4ꢁ,6ꢁ-tetra-O-acetyl-β-
D-glucopyranosyl)-1,6-dihydropyridin-2-yl)phenyl)-4-methylbenzenesulfona
mide (3a). Yield: 15%, as colorless crystals, mp: 116–118◦C. IR (KBr):
3255 cm−1 (NH), 2223 cm−1 (C≡N), 1743 cm−1 (C O, acetoxy), and

Synthesis and Antimicrobial Activity of 2-Pyridone Nucleosides
229
1642 cm−1 (C O, amide). 1H NMR (DMSO-d6): δ = 1.10 (d, J = 6.9 Hz,
6H, (CH3)2CH), 1.85, 1.95, 1.99, and 2.02 (4s, 12H, 4 CH3CO), 2.19 (s,
ꢁ
ꢁ
ꢁ
ꢁꢁ
3H, CH3), 2.84 (m, 1H, CH(CH3)2), 4.14 (dd, 1H, J 5 ,6 = 4.45, J 6 ,6
=
11.71 Hz, H-6ꢁ), 4.25 (dd, 1H, J 5 ,6 = 4.96, J 6 ,6 = 11.71 Hz, H-6ꢁꢁ), 4.91
ꢁ
ꢁ
ꢁ
ꢁꢁ
(m, 1H, H-5ꢁ), 5.07 (t, 1H, J = 9.22 Hz, H-4ꢁ), 5.27 (t, 1H, J 1 ,2 = 8.10,
ꢁ
ꢁ
J 2 ,3 = 9.58 Hz, H-2ꢁ), 5.49 (dd, 1H, J 2 ,3 = 9.58, J 3 ,4 = 9.22 Hz, H-3ꢁ),
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
6.20 (d, 1H, J 1 ,2 = 8.10 Hz, H-1ꢁ), 6.71 (s, 1H, pyridone-H-5), 7.12 (d,
2H, J = 8.42 Hz, Ar H), 7.21 (d, 2H, J = 8.32 Hz, Ar H), 7.53 (d, 2H,
J = 8.32 Hz, Ar H), 7.72 (d, 2H, J = 8.16 Hz, Ar H), 7.87 (d, 2H, J =
8.16 Hz, Ar H), 8.13 (d, 2H, J = 8.42 Hz, Ar H), 10.56 (s, 1H, NH). 13C
NMR (DMSO-d6): δ = 15.78 ((CH3)2CH), 20.07, 20.11, 20.14, and 20.18 (4
CH3CO), 20.32 (CH3), 30.4 (CH(CH3)2), 63.35 (C-6ꢁ), 65.7 (C-4ꢁ), 66.73
(C-3ꢁ), 68.75 (C-2ꢁ), 70.48 (C-5ꢁ), 91.25 (C-1ꢁ), 115.0 (C≡N), 119.3, 127.3,
128.2, 128.6, 129.1, 129.3, 130.2, 131.4, 133.6, 136.9, 137.0, 139.5, 141.0,
152.1, 158.1, 158.6 (Ar-C), 168.6, 169.0, 169.5, 170.0, and 171.2 (5 C O).
Anal. calcd for C42H43N3O12S (813.87): C, 61.98; H, 5.33; N, 5.16. Found:
C, 62.0; H, 5.35; N, 5.15.
ꢁ
ꢁ
N-(4-(5-Cyano-6-oxo-4-(thien-2-yl)-1-(2ꢁ,3ꢁ,4ꢁ,6ꢁ-tetra-O-acetyl-β-D-glucopy
ranosyl)-1,6-dihydropyridin-2-yl)phenyl)-4-methylbenzenesulfonamide (3b).
Yield: 13%, as colorless crystals, mp: 113–115◦C. IR (KBr): 3270 cm−1 (NH),
2224 cm−1 (C≡N), 1731 cm−1 (C O, acetoxy), and 1660 cm−1 (C O,
amide). 1H NMR (DMSO-d6): δ = 1.98, 1.99, 2.00, and 2.03 (4s, 12H, 4
ꢁ
ꢁ
ꢁ
ꢁꢁ
CH3CO), 2.20 (s, 3H, CH3), 3.98 (dd, 1H, J 5 ,6 = 4.77, J 6 ,6 = 11.53 Hz,
H-6ꢁ), 4.31 (dd, 1H, J 5 ,6 = 5.06, J 6 ,6 = 11.53 Hz, H-6ꢁꢁ), 5.0 (m, 1H, H-5ꢁ),
ꢁ
ꢁ
ꢁ
ꢁꢁ
5.28 (t, 1H, J = 9.42 Hz, H-4ꢁ), 5.47 (t, 1H, J 1 ,2 = 8.23, J 2 ,3 = 9.12 Hz,
ꢁ
ꢁ
ꢁ
ꢁ
H-2ꢁ), 5.83 (dd, 1H, J 2 ,3 = 9.12, J 3 ,4 = 9.41 Hz, H-3ꢁ), 6.49 (d, 1H, J 1 ,2
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
= 8.20 Hz, H-1ꢁ), 6.89 (s, 1H, pyridone-H-5), 7.15–7.83 (m, 10H, Ar H),
8.11 (dd, 1H, J = 4.24, 3.83 Hz, thiophene-H), 10.57 (s, 1H, NH). 13C NMR
(DMSO-d6): δ = 20.34, 20.72, 21.01, and 21.40 (4 CH3CO), 21.65 (CH3),
69.66 (C-6ꢁ), 70.47 (C-4ꢁ), 71.83 (C-3ꢁ), 72.04 (C-2ꢁ), 72.46 (C-5ꢁ), 91.23
(C-1ꢁ), 113.4, 115.0 (C≡N), 119.3, 127.1, 128.2, 128.7, 129.0, 129.3, 130.3,
131.0, 133.6, 137.0, 139.5, 141.0, 144.0, 148.7, 156.8, (Ar-C), 168.1, 169.3,
169.8, 170.0, and 170.3 (5 C O). Anal. calcd for C37H35N3O12S2 (777.82):
C, 57.13; H, 4.54; N, 5.40. Found: C, 57.10; H, 4.52; N, 5.39.
N-(4-(5-Cyano-4-(isopropylphenyl)-6-(β-D-glucopyranosyloxy)-1,6-
dihydropyridin-2-yl)phenyl)-4-methylbenzenesulfonamide (4a). Yield: 88%,
as colorless crystals from methanol, mp: 122–125◦C. IR (KBr): 3385 cm−1
(broad, 4OH), 3243 cm−1 (NH), and 2220 cm−1 (C≡N). 1H NMR (DMSO-
d6/D2O): δ = 1.11 (d, J = 6.9 Hz 6H, (CH3)2CH), 2.19 (s, 3H, CH3), 2.84
(m, 1H, CH(CH3)2), 3.63–3.49 (m, 6H, H-6ꢁ, H-6ꢁꢁ, H-5ꢁ, H-4ꢁ, H-3ꢁ and
H-2ꢁ), 4.50 (t, 1H, J = 4.02 Hz, OH-6ꢁ, D2O exchangeable), 4.68 (d, 1H, J =
4.21 Hz, OH-4ꢁ, D2O exchangeable), 5.12 (d, 1H, J = 5.12 Hz, OH-3ꢁ, D2O
exchangeable), 5.29 (d, 1H, J = 5.36 Hz, OH-2ꢁ, D2O exchangeable), 6.18
(d, 1H, J 1 ,2 = 8.18 Hz, H-1ꢁ), 7.02 (s, 1H, pyridone-H-5), 7.12 (d, 2H, J =
ꢁ
ꢁ

230
A. H. Moustafa et al.
8.42 Hz, Ar H), 7.21 (d, 2H, J = 8.32 Hz, Ar H), 7.53 (d, 2H, J = 8.32 Hz,
Ar H), 7.72 (d, 2H, J = 8.16 Hz, Ar H), 7.87 (d, 2H, J = 8.16 Hz, Ar H),
8.13 (d, 2H, J = 8.42 Hz, Ar H). Anal. calcd for C34H35N3O8S (645.72): C,
63.24; H, 5.46; N, 6.51. Found: C, 63.22; H, 5.47; N, 6.49.
N-(4-(5-Cyano-6-(β-D-glucopyranosyloxy)-4-(thien-2-yl)-1,6-dihydropyri
din-2-yl)phenyl)-4-methylbenzenesulfonamide (4b). Yield: 87%, as colorless
crystals from methanol, mp: 120–123◦C. IR (KBr): 3379 cm−1 (broad,
1
4OH), 3259 cm−1 (NH), and 2221 cm−1 (C≡N). H NMR (DMSO-d6): δ
= 2.32 (s, 3H, CH3), 3.65–3.48 (m, 6H, H-6ꢁ, H-6ꢁꢁ, H-5ꢁ, H-4ꢁ, H-3ꢁ and
H-2ꢁ), 4.60 (t, 1H, J = 3.46 Hz, OH-6ꢁ, D2O exchangeable), 5.09 (d, 1H, J =
4.31 Hz, OH-4ꢁ, D2O exchangeable), 5.16 (d, 1H, J = 4.28 Hz, OH-3ꢁ, D2O
exchangeable), 5.39 (d, 1H, J = 4.85 Hz, OH-2ꢁ, D2O exchangeable), 6.08
(d, 1H, J 1 ,2 = 8.16 Hz, H-1ꢁ), 7.01 (s, 1H, pyridone-H-5), 7.21–7.97 (m,
10H, Ar H), 8.10 (dd, 1H, J = 5.06, 4.43 Hz, thiophene-H), 10.25 (s, 1H,
NH, D2O exchangeable). Anal. calcd for C29H27N3O8S2 (609.67): C, 57.13;
H, 4.46; N, 6.89. Found: C, 57.15; H, 4.45; N, 6.92.
ꢁ
ꢁ
N-(4-(5-Cyano-4-(isopropylphenyl)-6-oxo-1-(β-D-glucopyranosyl)-1,6-
dihydropyridin-2-yl)phenyl)-4-methylbenzenesulfonamide (5a). Yield: 89%,
as colorless crystals from methanol, mp: 130–132◦C. IR (KBr): 3384 cm−1
(broad, 4OH), 3243 cm−1 (NH), 2222 cm−1 (C≡N), and 1644 cm−1 (C O,
1
amide). H NMR (DMSO-d6): δ = 1.12 (d, 6H, J = 6.9 Hz (CH3)2CH),
2.20 (s, 3H, CH3), 2.87 (m, 1H, CH(CH3)2), 3.35–3.40 (m, 6H, H-6ꢁ,
H-6ꢁꢁ, H-5ꢁ, H-4ꢁ, H-3ꢁ and H-2ꢁ), 4.46 (t, 1H, J = 4.01 Hz, OH-6ꢁ, D2O
exchangeable), 4.70 (d, 1H, J = 4.22 Hz, OH-4ꢁ, D2O exchangeable), 5.02
(d, 1H, J = 5.12 Hz, OH-3ꢁ, D2O exchangeable), 5.11 (d, 1H, J = 5.34 Hz,
OH-2ꢁ, D2O exchangeable), 6.12 (d, 1H, J 1 ,2 = 8.12 Hz, H-1ꢁ), 6.88 (s, 1H,
pyridone-H-5), 7.28 (d, 2H, J = 7.8 Hz, Ar H), 7.33 (d, 2H, J = 8.4 Hz,
Ar H), 7.41 (d, 2H, J = 8.4 Hz, Ar H), 7.69 (d, 2H, J = 8.10 Hz, Ar H),
7.84 (d, 2H, J = 8.10 Hz, Ar H), 8.24 (d, 2H, J = 7.8 Hz, Ar H), 10.75 (s,
1H, NH, D2O exchangeable). 13C NMR (DMSO-d6): δ = 15.7 ((CH3)2CH),
21.43 (CH3), 33.80 (CH(CH3)2), 61.1 (C-6ꢁ), 68.0 (C-2ꢁ), 70.1 (C-3ꢁ), 77.0
(C-4ꢁ), 78.3 (C-5ꢁ), 93.19 (C-1ꢁ), 115.4 (C≡N), 119.4, 127.1, 127.3, 128.6,
129.0, 130.0, 133.1, 133.9, 1351, 137.4, 141.0, 142.1, 145.3, 145.8, 155.1,
155.4, and 169.3 (Ar-C and C O amide). Anal. calcd for C34H35N3O8S
(645.72): C, 63.24; H, 5.46; N, 6.51. Found: C, 63.23; H, 5.44; N,
6.54.
ꢁ
ꢁ
N-(4-(5-Cyano-6-oxo-4-(thien-2-yl)-1-(β-D-glucopyranosyl)-1,6-dihydropy
ridin-2-yl)phenyl)-4-methylbenzenesulfonamide (5b). Yield: 85%, as color-
less crystals from methanol, mp: 127–129◦C. IR (KBr): 3427 cm−1 (broad,
4OH), 3260 cm−1 (NH) and 2218 cm−1 (C≡N), and 1655 cm−1 (C O,
1
amide). H NMR (DMSO-d6): δ = 2.31 (s, 3H, CH3), 3.64–3.50 (m, 6H,
H-6ꢁ, H-6ꢁꢁ, H-5ꢁ, H-4ꢁ, H-3ꢁ and H-2ꢁ), 4.60 (t, 1H, J = 3.46 Hz, OH-6ꢁ, D2O
exchangeable), 5.09 (d, 1H, J = 4.31 Hz, OH-4ꢁ, D2O exchangeable), 5.16
(d, 1H, J = 4.28 Hz, OH-3ꢁ, D2O exchangeable), 5.39 (d, 1H, J = 4.85 Hz,

Synthesis and Antimicrobial Activity of 2-Pyridone Nucleosides
231
OH-2ꢁ, D2O exchangeable), 6.18 (d, 1H, J 1 ,2 = 8.20 Hz, H-1ꢁ), 7.01 (s,
1H, pyridone-H-5), 7.20–7.98 (m, 10H, Ar H), 8.10 (dd, 1H, J = 5.06,
4.43 Hz, thiophene-H), 10.23 (s, 1H, NH, D2O exchangeable). Anal. calcd
for C29H27N3O8S2 (609.67): C, 57.13; H, 4.46; N, 6.89. Found: C, 57.16; H,
4.43; N, 6.90.
ꢁ
ꢁ
N-(4-(5-Cyano-4-(isopropylphenyl)-6-(2ꢁ,3ꢁ,4ꢁ,6ꢁ-tetra-O-acetyl-β-D-galac
topyranosyloxy)-1,6-dihydropyridin-2-yl)phenyl)-4-methylbenzenesulfonam
ide (6a). Yield: 59%, as colorless crystals, mp: 113–115◦C. IR (KBr):
3261 cm−1 (NH), 2226 cm−1 (C≡N), and 1755 cm−1 (C O, acetoxy). 1H
NMR (DMSO-d6): δ = 1.21 (d, J = 6.9 Hz, 6H, (CH3)2CH), 1.99, 2.00, 2.02,
and 2.03 (4s, 12H, 4 CH3CO), 2.31 (s, 3H, CH3), 2.96 (m, 1H, CH(CH3)2),
4.03 (dd, 1H, J 5 ,6 = 6.12, J 6 ,6 = 11.56 Hz, H-6ꢁ), 4.15 (dd, 1H, J 5 ,6
=
ꢁ
ꢁ
ꢁ
ꢁꢁ
ꢁ
ꢁꢁ
6.29, J 6 ,6 = 11.56 Hz, H-6ꢁꢁ), 4.68 (m, 1H, H-5ꢁ), 5.37 (t, 1H, J 3 ,2 = 10.50,
ꢁ
ꢁꢁ
ꢁ
ꢁ
J 3 ,4 = 2.84 Hz, H-3ꢁ), 5.43 (t, 1H, J 2 ,1 = 8.40, J 2 ,3 = 10.50 Hz, H-2ꢁ), 5.52
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
(t, 1H, J 4 ,3 = 2.85, J 4 ,5 = 3.30 Hz, H-4ꢁ), 6.57 (d, 1H, J 1 ,2 = 8.40 Hz,
H-1ꢁ), 6.87 (s, 1H, pyridone-H-5), 7.26 (d, 2H, J = 7.8 Hz, Ar H), 7.32 (d,
2H, J = 8.4 Hz, Ar H), 7.42 (d, 2H, J = 8.4 Hz, Ar H), 7.68 (d, 2H, J =
8.10 Hz, Ar H), 7.85 (d, 2H, J = 8.10 Hz, Ar H), 8.24 (d, 2H, J = 7.8 Hz,
Ar H), 10.72 (s, 1H, NH). 13C NMR (DMSO-d6): δ = 15.8 ((CH3)2CH),
20.15, 20.36, 20.93, and 21.0 (4 CH3CO), 23.64 (CH3), 33.36 (CH(CH3)2),
61.8 (C-6ꢁ), 67.6 (C-4ꢁ), 70.2 (C-2ꢁ), 71.2 (C-3ꢁ), 71.8 (C-5ꢁ), 93.9 (C-1ꢁ),
114.9 (C≡N), 118.8, 126.6, 126.8, 128.6, 128.7, 129.7, 1311, 133.1, 136.5,
137.0 140.5, 142.2, 143.5, 150.7, 156.1, 156.6, 161.7 (Ar-C and C N),
168.7, 169.5, 169.7, and 170.0 (4 C O). Anal. calcd for C42H43N3O12S
(813.87): C, 61.98; H, 5.33; N, 5.16. Found: C, 61.95; H, 5.31; N,
5.18.
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
N-(4-(5-Cyano-6-(2ꢁ,3ꢁ,4ꢁ,6ꢁ-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-
(thien-2-yl)-1,6-dihydropyridin-2-yl)phenyl)-4-methylbenzenesulfonamide
(6b). Yield: 62%, as colorless crystals, mp: 109–111◦C. IR (KBr): 3267 cm−1
1
(NH), 2218 cm−1 (C≡N), and 1738 cm−1 (C O, acetoxy). H NMR
(DMSO-d6): δ = 1.98, 2.01, 2.03, and 2.05 (4s, 12H, 4 CH3CO), 2.32 (s,
3H, CH3), 4.02 (dd, 1H, J 5 ,6 = 6.12, J 6 ,6 = 11.57 Hz, H-6ꢁ), 4.13 (dd, 1H,
ꢁ
ꢁ
ꢁ
ꢁꢁ
J 5 ,6 = 6.29, J 6 ,6 = 11.57 Hz, H-6ꢁꢁ), 4.68 (m, 1H, H-5ꢁ), 5.36 (t, 1H, J 3 ,2
ꢁ
ꢁ
ꢁ
ꢁꢁ
ꢁ
ꢁ
= 10.50, J 3 ,4 = 2.84 Hz, H-3ꢁ), 5.43 (t, 1H, J 2 ,1 = 8.40, J 2 ,3 = 10.50 Hz,
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
H-2ꢁ), 5.53 (t, 1H, J 4 ,3 = 2.85, J 4 ,5 = 3.30 Hz, H-4ꢁ), 6.48 (d, 1H, J 1 ,2
=
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
8.40 Hz, H-1ꢁ), 6.88 (s, 1H, pyridone-H-5), 7.30–7.90 (m, 10H, Ar H), 8.24
(dd, 1H, J = 4.24, 3.85 Hz, thiophene-H), 10.65 (s, 1H, NH). Anal. calcd
for C37H35N3O12S2 (777.82): C, 57.13; H, 4.54; N, 5.40. Found: C, 57.11; H,
4.53; N, 5.43.
N-(4-(5-Cyano-4-(isopropylphenyl)-6-oxo-1-(2ꢁ,3ꢁ,4ꢁ,6ꢁ-tetra-O-acetyl-β-D-
galactopyranosyl)-1,6-dihydropyridin-2-yl)phenyl)-4-methylbenzenesulfona
mide (7a−).1 Yield: 16%, as colorless crystals, mp: 119–121◦C. IR (KBr):
3260 cm (NH), 2226 cm−1 (C≡N), 1755 cm−1 (C O, acetoxy), and
1699 cm−1 (C O, amide). 1H NMR (DMSO-d6): δ = 1.21 (d, J = 6.9 Hz,

232
A. H. Moustafa et al.
6H, ((CH3)2CH), 1.99, 2.0, 2.02, and 2.03 (4s, 12H, 4 CH3CO), 2.31 (s, 3H,
ꢁ
ꢁ
ꢁ
ꢁꢁ
CH3), 2.96 (m, 1H, CH(CH3)2), 4.03 (dd, 1H, J 5 ,6 = 6.12, J 6 ,6 = 11.56 Hz,
H-6ꢁ), 4.15 (dd, 1H, J 5 ,6 = 6.30, J 6 ,6 = 11.56 Hz, H-6 ), 4.68 (m, 1H, H-5 ),
ꢁꢁ
ꢁ
ꢁ
ꢁꢁ
ꢁ
ꢁꢁ
5.37 (t, 1H, J 3 ,2 = 10.48, J 3 ,4 = 2.85 Hz, H-3ꢁ), 5.43 (t, 1H, J 2 ,1 = 8.23,
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
J 2 ,3 = 10.48 Hz, H-2ꢁ), 5.52 (t, 1H, J 4 ,3 = 2.85, J 4 ,5 = 3.30 Hz, H-4ꢁ), 6.35
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
(d, 1H, J 1 ,2 = 8.23 Hz, H-1ꢁ), 6.87 (s, 1H, pyridone-H-5), 7.26 (d, 2H, J =
7.8 Hz, Ar H), 7.32 (d, 2H, J = 8.4 Hz, Ar H), 7.42 (d, 2H, J = 8.4 Hz,
Ar H), 7.68 (d, 2H, J = 8.10 Hz, Ar H), 7.85 (d, 2H, J = 8.10 Hz, Ar H),
8.24 (d, 2H, J = 7.8 Hz, Ar H), 10.72 (s, 1H, NH). 13C NMR (DMSO-d6):
δ = 15.8 ((CH3)2CH), 20.15, 20.36, 20.93, and 21.0 (4 CH3CO), 23.64
(CH3), 33.36 (CH(CH3)2), 61.8 (C-6ꢁ), 67.6 (C-4ꢁ), 70.2 (C-2ꢁ), 71.2 (C-3ꢁ),
71.8 (C-5ꢁ), 89.91 (C-1ꢁ), 114.8 (C≡N), 118.8, 126.6, 126.8, 128.6, 128.7,
129.7, 131.1, 133.1, 136.5, 137.0 140.5, 142.2, 143.5, 150.7, 156.1, and 156.6
(Ar-C), 168.2, 169.0, 169.5, 169.7, and 170.0 (5 C O). Anal. calcd for
C42H43N3O12S (813.87): C, 61.98; H, 5.33; N, 5.16. Found: C, 61.97; H, 5.30;
N, 5.15.
ꢁ
ꢁ
N-(4-(5-Cyano-6-(2ꢁ,3ꢁ,4ꢁ,6ꢁ-tetra-O-acetyl-β-D-galactopyranosyl)-4-(thien-
2-yl)-1,6-dihydropyridin-2-yl)phenyl)-4-methylbenzenesulfonamide
(7b).
Yield: 12%, as colorless crystals, mp: 118–120◦C. IR (KBr): 3262 cm−1 (NH),
2218 cm−1 (C≡N), and 1748 cm−1 (C O, acetoxy) and 1685 cm−1 (C O,
1
amide). H NMR (DMSO-d6): δ = 1.98, 2.02, 2.03, and 2.04 (4s, 12H, 4
ꢁ
ꢁ
ꢁ
ꢁꢁ
CH3CO), 2.31 (s, 3H, CH3), 4.03 (dd, 1H, J 5 ,6 = 6.12, J 6 ,6 = 11.56 Hz,
H-6ꢁ), 4.14 (dd, 1H, J 5 ,6 = 6.30, J 6 ,6 = 11.56 Hz, H-6 ), 4.67 (m, 1H, H-5 ),
ꢁꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁꢁ
5.38 (t, 1H, J 3 ,2 = 10.49, J 3 ,4 = 2.85 Hz, H-3ꢁ), 5.44 (t, 1H, J 2 ,1 = 8.38, J 2 ,3
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
= 10.49 Hz, H-2ꢁ), 5.51 (t, 1H, J 4 ,3 = 2.85, J 4 ,5 = 3.30 Hz, H-4ꢁ), 6.42 (d,
ꢁ
ꢁ
ꢁ
ꢁ
1H, J 1 ,2 = 8.38 Hz, H-1ꢁ), 6.89 (s, 1H, pyridone-H-5), 7.23–7.89 (m, 10H,
Ar H), 8.25 (dd, 1H, J = , 3.85, 3.39 Hz, thiophene-H), 10.68 (s, 1H, NH).
Anal. calcd for C37H35N3O12S2 (777.82): C, 57.13; H, 4.54; N, 5.40. Found:
C, 57.10; H, 4.55; N, 5.42.
ꢁ
ꢁ
N-(4-(5-Cyano-4-(isopropylphenyl)-6-(β-D-galactopyranosyloxy)-1,6-
dihydropyridin-2-yl)phenyl)-4-methylbenzenesulfonamide (8a). Yield: 86%,
as colorless crystals from methanol, mp: 124–126◦C. IR (KBr): 3419 cm−1
(broad, 4OH), 3240 cm−1 (NH), and 2224 cm−1 (C≡N). 1H NMR (DMSO-
d6): δ = 1.24 (d, J = 6.9 Hz, 6H, ((CH3)2CH), 2.32 (s, 3H, CH3), 2.98 (m,
1H, CH(CH3)2), 3.67 (m, 3H, H-3ꢁ, H-6ꢁ, and H-6ꢁꢁ), 3.73 (m, 3H, H-2ꢁ,
H-4ꢁ, and H-5ꢁ), 4.61 (m, 2H, OH-4ꢁ, OH-6ꢁ, D2O exchangeable), 4.90 (d,
1H, J = 5.21 Hz, OH-3ꢁ, D2O exchangeable), 5.28 (d, 1H, J = 4.48 Hz,
OH-2ꢁ, D2O exchangeable), 6.06 (d, 1H, J 1 ,2 = 8.32 Hz, H-1ꢁ), 6.92 (s,
1H, pyridone-H-5), 7.19 (d, 2H, J = 7.89 Hz, Ar H), 7.27 (d, 2H, J =
8.34 Hz, Ar H), 7.34 (d, 2H, J = 8.34 Hz, Ar H), 7.60 (d, 2H, J = 8.12 Hz,
Ar H), 7.65 (d, 2H, J = 8.12 Hz, Ar H), 8.11 (d, 2H, J = 7.89 Hz, Ar H),
10.64 (s, 1H, NH, D2O exchangeable). Anal. calcd for C34H35N3O8S
(645.72): C, 63.24; H, 5.46; N, 6.51. Found: C, 63.22; H, 5.45; N,
6.48.
ꢁ
ꢁ

Synthesis and Antimicrobial Activity of 2-Pyridone Nucleosides
233
N-(4-(5-Cyano-6-(β-D-galactopyranosyloxy)-4-(thien-2-yl)-1,6-dihydropy
ridin-2-yl)phenyl)-4-methylbenzenesulfonamide (8b). Yield: 87%, as color-
less crystals from methanol, mp: 125–127◦C. IR (KBr): 3420 cm−1 (broad,
4OH), 3245 cm−1 (NH), and 2219 cm−1 (C≡N). 1H NMR (DMSO-d6/D2O):
δ = 2.31 (s, 3H, CH3) 3.65 (m, 3H, H-3ꢁ, H-6ꢁ, and H-6ꢁꢁ), 3.80 (m, 3H,
H-2ꢁ, H-4ꢁ, and H-5ꢁ), 6.27 (d, 1H, J 1 ,2 = 8.23 Hz, H-1ꢁ), 6.85 (s, 1H,
pyridone-H-5), 7.26–7.91 (m, 10H, Ar H), 8.24 (dd, 1H, J = 5.08, 3.83 Hz,
thiophene-H). Anal. calcd for C29H27N3O8S2 (609.67): C, 57.13; H, 4.46; N,
6.89. Found: C, 57.12; H, 4.45; N, 6.87.
ꢁ
ꢁ
N-(4-(5-Cyano-4-(isopropylphenyl)-6-oxo-1-(β-D-galactopyranosyl)-1,6-
dihydropyridin-2-yl)phenyl)-4-methylbenzenesulfonamide (9a). Yield: 88%,
◦
as colorless crystals from methanol, mp: 132–134 C. IR (KBr): 3391 cm−1
(broad, 4OH), 3240 cm−1 (NH), and 2225 cm−1 (C≡N), 1646 cm−1
1
(C O, amide). H NMR (DMSO-d6/D2O): δ = 1.23 (d, J = 6.9 Hz, 6H,
((CH3)2CH)), 2.32 (s, 3H, CH3), 2.98 (m, 1H, CH(CH3)2), 3.68 (m, 3H,
H-3ꢁ, H-6ꢁ, and H-6ꢁꢁ), 3.79 (m, 3H, H-2ꢁ, H-4ꢁ, and H-5ꢁ), 6.03 (d, 1H, J 1 ,2
=
ꢁ
ꢁ
8.20 Hz, H-1ꢁ), 6.90 (s, 1H, pyridone-H-5), 7.18 (d, 2H, J = 7.89 Hz, Ar H),
7.27 (d, 2H, J = 8.34 Hz, Ar H), 7.32 (d, 2H, J = 8.34 Hz, Ar H), 7.61 (d,
2H, J = 8.12 Hz, Ar H), 7.66 (d, 2H, J = 8.12 Hz, Ar H), 8.12 (d, 2H, J =
7.89 Hz, Ar H). Anal. calcd for C34H35N3O8S (645.72): C, 63.24; H, 5.46;
N, 6.51. Found: C, 63.22; H, 5.47; N, 6.53.
N-(4-(5-Cyano-6-oxo-4-(thien-2-yl)-1-(β-D-galactopyranosyl)-1,6-dihydro
pyridin-2-yl)phenyl)-4-methylbenzenesulfonamide (9b). Yield: 89%, as
colorless crystals from methanol, mp: 130–132◦C. IR (KBr): 3432 cm−1
(broad, 4OH), 3240 cm−1 (NH), and 2221 cm−1 (C≡N), 1665 cm−1 (C O,
1
amide). H NMR (DMSO-d6/D2O): δ = 2.32 (s, 3H, CH3) 3.67 (m, 3H,
H-3ꢁ, H-6ꢁ, and H-6ꢁꢁ), 3.81 (m, 3H, H-2ꢁ, H-4ꢁ, and H-5ꢁ), 6.28 (d, 1H, J 1 ,2
=
ꢁ
ꢁ
8.20 Hz, H-1ꢁ), 6.82 (s, 1H, pyridone-H-5), 7.23–7.89 (m, 10H, Ar H), 8.23
(dd, 1H, J = 5.08, 3.83 Hz,thiophene-H). Anal. calcd for C29H27N3O8S2
(609.67): C, 57.13; H, 4.46; N, 6.89. Found: C, 57.10; H, 4.44; N,
6.92.
N-(4-(5-Cyano-6-(2ꢁ,3ꢁ,4ꢁ,6ꢁ-tetra-O-acetyl-β-D-galactopyranosyl-(1→4)-
(2ꢁ,3ꢁ,6ꢁ-tri-O-acetyl-β-D-glucopyranosyloxy)-4-(thien-2-yl)-1,6-dihydropyri
din-2-yl)phenyl)-4-methylbenzenesulfonamide (10). Yield: 52%, as colorless
crystals, mp: 124–126◦C. IR (KBr): 3249 cm−1 (NH), 2219 cm−1 (C≡N),
and 1747 cm−1 (C O, acetoxy). 1H NMR (DMSO-d6): δ = 1.90, 1.91, 1.96,
2.00, 2.02, 2.04, and 2.11 (7s, 21H, 7 CH3CO), 2.32 (s, 3H, CH3), 3.98–4.06
(m, 3H, H-2ꢁb, H-6ꢁa, H-6ꢁb), 4.89 (dd, 1H, J 6 a,6 a = 11.87, J 6 a,5 a = 5.52 Hz,
ꢁꢁ
ꢁ
ꢁꢁ
ꢁ
H-6ꢁꢁa), 4.90 (m, 1H, H-5ꢁb), 4.92 (dd, 1H, J 6 b,5 b = 6.46 Hz, H-6ꢁꢁb), 4.93
ꢁꢁ
ꢁ
(m, 1H, H-5ꢁa), 5.24 (d, 1H, J 1 b,2 b = 7.65 Hz, H-1ꢁb), 5.25 (dd, 1H, J 4 b,3 b
=
ꢁ
ꢁ
ꢁ
ꢁ
3.23, J 4 b,5 b = 3.98 Hz, H-4ꢁb), 5.26 (dd, 1H, J 2 a,1 a = 8.72, J 2 a,3 a = 8.40 Hz,
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
H-2ꢁa), 5.33 (dd, 1H, J 4 a,3 a = 9.13, J 4 a,5 a = 9.90 Hz, H-4ꢁa), 5.40 (dd,
ꢁ
ꢁ
ꢁ
ꢁ
1H, J 3 b,4 b = 3.23, J 3 b,2 b = 8.87 Hz, H-3ꢁb), 5.62 (dd, 1H, J 3 a,2 a = 8.40,
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
J 3 a,4 a = 9.13 Hz, H-3ꢁa), 6.65 (d, 1H, J 1 a,2 a = 8.72 Hz, H-1ꢁa), 6.95 (s, 1H,
ꢁ
ꢁ
ꢁ
ꢁ

234
A. H. Moustafa et al.
pyridone-H-5), 7.23–7.90 (m, 10H, Ar H), 8.23 (dd, 1H, J = 5.08, 3.93 Hz,
thiophene-H), 10.65 (s, 1H, NH). 13C NMR (DMSO-d6): δ = 20.1, 20.41,
20.45, 20.49, 20.57, 20.95, and 21.01 (7 CH3CO), 30.29 (CH3), 60.8 (C-6ꢁb),
62.1 (C-6ꢁa), 66.2 (C-4ꢁb), 68.2 (C-2ꢁb), 68.5 (C-2ꢁa), 69.6 (C-5ꢁb), 70.1
(C-3ꢁb), 70.3 (C-3ꢁa), 70.8 (C-4ꢁa), 72.2 (C-5ꢁa), 89.4 (C-1ꢁb), 94.1 (C-1ꢁa).
112.8, 114.7 (C≡N), 118.7, 126.7, 128.6, 128.9, 129.8, 130.5, 130.7, 131.1,
133.0, 136.3, 136.5, 140.5, 143.5, 148.2, 156.3, and 162.2 (Ar-C and C N),
169.1, 169.3, 169.6, 170.0, 170.4, 172.3, and 172.7 (7 C O). Anal. calcd for
C49H51N3O20S2 (1066.07): C, 55.21; H, 4.82; N, 3.94. Found: C, 55.18; H,
4.85; N, 3.92.
N-(4-(5-Cyano-6-oxo-4-(thien-2-yl)-1-(2ꢁ,3ꢁ,4ꢁ,6ꢁ-tetra-O-acetyl-β-D-galacto
pyranosyl-(1→4)-(2ꢁ,3ꢁ,6ꢁ-tri-O-acetyl-β-D-glucopyranosyl)-1,6-dihydropyri
din-2-yl)phenyl)-4-methylbenzenesulfonamide (11). Yield: 11%, as colorless
crystals, mp: 133–135◦C. IR (KBr): 3249 cm−1 (NH), 2223 cm−1 (C≡N),
1
1743 cm−1 (C O, acetoxy), and 1642 cm−1 (C O, amide). H NMR
(DMSO-d6): δ = 1.90, 1.91, 1.96, 2.00, 2.02, 2.04, and 2.11 (7s, 21H, 7
CH3CO), 2.32 (s, 3H, CH3), 3.98–4.06 (m, 3H, H-2ꢁb, H-6ꢁa, H-6ꢁb), 4.89
(dd, 1H, J 6 a,6 a = 11.87, J 6 a,5 a = 5.52 Hz, H-6ꢁꢁa), 4.90 (m, 1H, H-5ꢁb),
ꢁꢁ
ꢁ
ꢁꢁ
ꢁ
4.92 (dd, 1H, J 6 b,5 b = 6.46 Hz, H-6ꢁꢁb), 4.93 (m, 1H, H-5ꢁa), 5.24 (d, 1H,
ꢁꢁ
ꢁ
J 1 b,2 b = 7.65 Hz, H-1ꢁb), 5.25 (dd, 1H, J 4 b,3 b = 3.23, J 4 b,5 b = 3.98 Hz,
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
H-4ꢁb), 5.26 (dd, 1H, J 2 a,1 a = 8.72, J 2 a,3 a = 8.40 Hz, H-2ꢁa), 5.33 (dd, 1H,
ꢁ
ꢁ
ꢁ
ꢁ
J 4 a,3 a = 9.13, J 4 a,5 a = 9.90 Hz, H-4ꢁa), 5.40 (dd, 1H, J 3 b,4 b = 3.23, J 3 b,2 b
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
= 8.87 Hz, H-3ꢁb), 5.62 (dd, 1H, J 3 a,2 a = 8.40, J 3 a,4 a = 9.13 Hz, H-3ꢁa),
ꢁ
ꢁ
ꢁ
ꢁ
6.65 (d, 1H, J 1 a,2 a = 8.72 Hz, H-1ꢁa), 6.95 (s, 1H, pyridone-H-5), 7.23–7.90
(m, 10H, Ar H), 8.23 (dd, 1H, J = 5.08, 3.93 Hz, thiophene-H), 10.65
(s, 1H, NH). 13C NMR (DMSO-d6): δ = 20.1, 20.41, 20.45, 20.49, 20.57,
20.95, and 21.01 (7 CH3CO), 30.29 (CH3), 60.8 (C-6ꢁb), 62.1 (C-6ꢁa), 66.2
(C-4ꢁb), 68.2 (C-2ꢁb), 68.5 (C-2ꢁa), 69.6 (C-5ꢁb), 70.1 (C-3ꢁb), 70.3 (C-3ꢁa),
70.8 (C-4ꢁa), 72.2 (C-5ꢁa), 80.9 (C-1ꢁa), 89.0 (C-1ꢁb). 112.8, 114.7 (C≡N),
118.7, 126.7, 128.6, 128.9, 129.8, 130.5, 130.7, 131.1, 133.0, 136.3, 136.5,
140.5, 143.5, 148.2, and 156.3 (Ar-C and C N), 167.8, 169.1, 169.3, 169.6,
170.0, 170.4, 172.3, and 172.7 (8 C O). Anal. calcd for C49H51N3O20S2
(1066.07): C, 55.21; H, 4.82; N, 3.94. Found: C, 55.19; H, 4.83; N,
3.92.
ꢁ
ꢁ
N-(4-(5-Cyano-6-(β-D-galactopyranosyl-(1→4)-(β-D-glucopyranosyloxy)-
4-(thien-2-yl)-1,6-dihydropyridin-2-yl)phenyl)-4-methylbenzenesulfonamide
(12). Yield: 88%, as colorless crystals from methanol, mp: 143–145◦C. IR
(KBr): 3385 cm−1 (7 OH), 3242 cm−1 (NH), and 2220 cm−1 (C≡N). 1H
NMR (DMSO-d6/D2O): δ = 2.12 (s, 3H, CH3), 3.50–3.65 (4 m, 12H, H-2ꢁb,
H-3ꢁb, H-4ꢁb, H-5ꢁb, H-6ꢁb, H-6ꢁꢁb, H-2ꢁa, H-3ꢁa, H-4ꢁa, H-5ꢁa, H-6ꢁa, and
H-6ꢁꢁa), 5.67 (d, 1H, J 1 b,2 b = 7.85 Hz, H-1ꢁb), 5.97 (d, 1H, J 1 a,2 a = 8.86 Hz,
H-1ꢁa), 6.98 (s, 1H, pyridone-H-5), 7.10–7.84 (m, 10H, Ar H), 8.11 (dd, 1H,
J = 5.23, 4.21 Hz, thiophene-H). Anal. calcd for C35H37N3O13S2 (771.81):
C, 54.47; H, 4.83; N, 5.44. Found: C, 54.48; H, 4.84; N, 5.45.
ꢁ
ꢁ
ꢁ
ꢁ

Synthesis and Antimicrobial Activity of 2-Pyridone Nucleosides
235
N-(4-(5-Cyano-6-oxo-4-(thien-2-yl)-1-(β-D-galactopyranosyl-(1→4)-(β-D-
glucopyranosyl)-1,6-dihydropyridin-2-yl)phenyl)-4-methylbenzenesulfonam
ide (13). Yield: 86%, as colorless crystals from methanol, mp: 152–154◦C.
IR (KBr): 3391 cm−1 (7 OH), 3238 cm−1 (NH), 2225 cm−1 (C≡N), and
1646 cm−1 (C O, amide). 1H NMR (DMSO-d6/D2O): δ = 2.12 (s, 3H,
CH3), 3.50–3.65 (4 m, 12H, H-2ꢁb, H-3ꢁb, H-4ꢁb, H-5ꢁb, H-6ꢁb, H-6ꢁꢁb, H-2ꢁa,
H-3ꢁa, H-4ꢁa, H-5ꢁa, H-6ꢁa, and H-6ꢁꢁa), 5.67 (d, 1H, J 1 b,2 b = 7.85 Hz, H-1ꢁb),
ꢁ
ꢁ
5.88 (d, 1H, J 1 a,2 a = 8.83 Hz, H-1ꢁa), 6.98 (s, 1H, pyridone-H-5), 7.10–7.84
(m, 10H, Ar H), 8.11 (dd, 1H, J = 5.23, 4.21 Hz, thiophene-H). Anal. calcd
for C35H37N3O13S2 (771.81): C, 54.47; H, 4.83; N, 5.44. Found: C, 54.49; H,
4.85; N, 5.43.
ꢁ
ꢁ
Biological Activity
The antimicrobial activity of the synthetic compounds were evaluated
against fungi, namely (Aspergillus niger and Candida albicans) and antibac-
terial, namely (Staphylococcus aureus and Staphylococcus epidermidis) (Gram
+ve) and (Escherichia Coli, Klebsiella Pneumoniae and Pseudomonas aeruginosa)
(Gram –ve) as stock cultures in the Microbiology Department, Faculty of
Pharmacy, Zagazig Univesity using the well diffusion method.[37] After seed-
ing of the cooled-solid medium by the microbial suspension and pouring
in sterile plates, the cultures were incubated overnight for pre-germination,
and then 300 μg of each tested compound was pipette to the wells of the
plate cultures. Blanks of dissolving solvent were made. The cultures were
incubated for 7 days at 30◦C for fungal growth and for 2 days at 37◦C for
bacterial growth. The antimicrobial activity was expressed by the diameter of
TABLE 1 Antibacterial activities of some new synthesized compounds
Inhibition zone (mm)
Gram (+ve)
Gram (−ve)
Comp.
No.
S. aureus
ATCC6538
S. epidermidis
ATCC12228
E. coli
ATCC10536
K. pneumoniae
ATCC27736
P. aeruginosa
ATCC9022
2a
3b
4b
5a
6a
7b
8a
9a
18
19
21
22
19
21
22
21
19
20
20
18
20
20
22
18
20
22
22
19
19
19
17
18
16
18
17
17
19
18
18
18
16
17
18
20
21
17
20
19
16
19
16
15
16
16
17
17
17
17
17
17
16
18
15
10
12
Amoxycillin (300 μg/mL)

236
A. H. Moustafa et al.
TABLE 2 Antifungal activities of some new synthesized compounds
Inhibition zone (mm)
Fungi
Comp.
No.
C. albicans
ATCC10231
A. niger
ATCC 16404
2a
3b
4b
5a
6a
7b
8a
9a
20
18
20
18
20
21
19
20
17
18
16
18
18
21
21
21
19
20
20
19
20
14
10
12
Amphotericin B
(300 μg/mL)
inhibitory zone comparing to amoxycillin and amphotericin B as standard
antibacterial and antifungal agents, respectively.
Antimicrobial Activity
It clearly observed from the obtained data in Table 1, the tested com-
pounds 4b, 5a, 7b, 8a, 9a, and 12 showed significant antibacterial activity
against Gram (+ve) (S. aureus and S. epidermidis) and significant antibacte-
rial activity against (E. coli, K. Pneumoniae, and P. aeruginosa) as Gram (−ve)
using the well diffusion method[38] compared with amoxycillin as standard.
Compounds 2a, 3b, 6a, and 10 were showed higher activity against Gram
(+ve) and Gram (−ve) compared with Amoxycillin. For antifungal activity,
in Table 2, it was observed that all the tested compounds have a significant
antifungal activity against (A. niger) and (C. albicans) than the standard drug
Amphotericin B.
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