Synthesis and Antibacterial Activity of Novel 3-N-Substituted 1,8-Naphthyridin-2(1H)-ones

Article abstract of DOI:10.1134/S1070363219120338

Synthesis of novel N-protected and unprotected 3-N-substituted 1,8-naphthyridin-2(1H)-ones with potential inhibiting activity of penicillin-binding protein 6 (PBP6) has been developed. The synthesis is designed around a Buchwald–Hartwig crosscoupling of v

Full text of DOI:10.1134/S1070363219120338

ISSN 1070-3632, Russian Journal of General Chemistry, 2019, Vol. 89, No. 12, pp. 2534–2543. © Pleiades Publishing, Ltd., 2019.
Synthesis and Antibacterial Activity
of Novel 3-N-Substituted 1,8-Naphthyridin-2(1H)-ones
a,
a
a
a
a
a
B. Sakram *, A. Kurumanna , K. Ashok , S. Rambabu , D. Ravi , and B. Sathish Kumar
a
Department of Chemistry, Osmania University, Tarnaka, Hyderabad, Telangana, 500007 India
*
e-mail: bschemou@gmail.com
Received July 2, 2019; revised September 7, 2019; accepted September 30, 2019
Abstract—Synthesis of novel N-protected and unprotected 3-N-substituted 1,8-naphthyridin-2(1H)-ones with
potential inhibiting activity of penicillin-binding protein 6 (PBP6) has been developed. The synthesis is designed
around a Buchwald–Hartwig crosscoupling of various 3-bromo-6-substituted-1,8-naphthyridin-2(1H)-ones with
two different functionalized anilines. According to the preliminary antibacterial evaluation, the products 9b–9d
and 10b–10d have demonstrated high inhibiting activity against spore germination of Staphylococcus aureus
(gram positive) and Escherichia coli (gram negative). The molecular docking procedure has denoted the probable
interactions of the synthesized compounds 9b–9d and 10b–10d with the target protein.
Keywords: naphthyridines, Buchwald–Hartwig cross-coupling, antibacterial activity, penicillin-binding protein
6
(PBP6), docking analysis
DOI: 10.1134/S1070363219120338
Naphthyridines that are fused nitrogen heterocycles
of natural and synthetic origin exhibit various biological
activities [1], including anticancer [2–4], antibacterial [5],
and antimalarial [6]. In this respect, we present herein
development of synthetic approach to 1,8-naphthyridine
derivatives by the Buchwald–Hartwig cross-coupling
reaction of 3-halo-1,8-naphthyridine derivatives with
anilines and their antibacterial activity.
do-1-(4-methoxybenzyl)-1,8-naphthyridin-2(1H)-one (7).
Reaction of the derivative 6 with isocyanuric acid in the
presence of sodium cyanate in the media of AcOH–H O
2
(3:1) led to 1-[6-bromo-8-(4-methoxybenzyl)-7-oxo-7,8-
dihydro-1,8-naphthyridin-3-yl]urea (8a). Derivatives 8b,
8
c, and 8d were formed in the reactions of compound 7
with different substituted 6-cyano/meta methoxy phenyl/
ethoxy-3-bromo-1-(4-methoxybenzyl)-1,8-naphthyridin-
2
(1H)-ones (Scheme 2).
RESULTS AND DISCUSSION
3
-Anilino-1,8-naphthyridin-2(1H)-ones 9a–9e were
Herein, we report the synthesis of novel efficient
N-protected and unprotected 3-N substituted 1, 8-naph-
thyridin-2(1H)-ones (Schemes 1–3). Pyridine-2-amino-
synthesized by the cross-coupling reaction of N-PMB pro-
tected 3-bromo substituted 1,8-naphthyridin-2(1H)-ones
a–8d with substituted anilines (Scheme 3). This method
proved to be highly efficient and a reliable alternative to
the catalyzed processes. Treatment of compounds 9a–9e
with trifluoromethanesulfonic acid in trifluoroacetic acid
resulted in removal of the protecting group and formation
of the desired novel 3-anilino-1,8-naphthyridin-2(1H)-
ones 10a–10e in high yields (Scheme 3).
8
3
-aldehyde 1 was reacted with 2-bromo diethylphosphono
acetic acid 2 in presence of LiCl and DBU to produce
-bromo-1,8-naphthyridin-2(1H)-one 3, which was
nitrated under standard conditions to give 3-bromo-
3
6
4
-nitro-1,8-naphthyridin-2(1H)-one 4. The compound
was protected by p-methoxybenzyl chloride with
formation of 3-bromo-1-(4-methoxybenzyl)-6-nitro-1,8-
naphthyridin-2(1H)-one 5 (yield 91%). Its following
reaction with zinc powder in acetic acid and methanol
Substitution on the aromatic ring influenced the yields
of products (Table 1). Electron-donating groups on
(1:3) at room temperature gave 6-amino-3-bromo-1-(4-
1
,8-naphthyridin-2(1H)-ones led to lower yields of com-
methoxybenzyl)-1,8-naphthyridin-2(1H)-one 6 (yield
pounds 8a, 8c, 8d, 9a, 9b, 9d, 9e, 10a, 10b, 10d, and 10e.
Presence of the electron-withdrawing groups resulted in
good yields of products 8b, 9c, and 10c. To the best of our
knowledge, that was the first synthesis of N-protected and
7
8%) (Scheme 1).
The compound 6 was treated with KI in the presence of
NaNO and concentrated HCl to produced 3-bromo-6-io-
2
2
534

SYNTHESIS AND ANTIBACTERIAL ACTIVITY
2535
Scheme 1. Synthesis of 3-bromo substituted 1,8-naphthyridin-2(1H)-one (6).
O
O
P
HO
O
O
Br
O
2
O N
Br
O
Br
O
2
H
1
2
N
N
N
NH2
N
N
H
H
1
3
4
H N
Br
O N
Br
2
2
3
4
N
N
O
N
N
O
PMB
PMB
5
6
Reagents and conditions: (1) LiCl, DBU, THF; (2) HNO , H SO ; (3) PMB-Cl, K CO , DMF; (4) Zn, AcOH, MeOH.
3
2
4
2
3
unprotected 3-N substituted 1,8-naphthyridin-2(1H)-ones
positive (Staphylococcus aureus,) and Gram-negative
(Escherichia coli,) bacterial pathogens were used in the
study. Results were compared with the standard drug
ciprofloxacin. DMSO was used as a solvent control. Dif-
ferences in activity of the synthesized compounds indi-
cated the importance of the amine linker and substituted
urea, methoxy phenzyl, cyano, and ethoxy in N-PMB
protected 3-anilino1,8-naphthyridin-2(1H)-ones and
by this method. Structures of the synthesized compounds
1
were confirmed by H NMR and LCMS spectra.
Antibacterial activity. Antibacterial activity of N-PMB
protected 3-anilino1,8-naphthyridin-2(1H)-ones (9a–9e)
and 3-anilino-1,8-naphthyridine-2(1H)-ones (10a–10e)
were evaluated as minimum inhibitory concentrations
(
MIC) by the disc-diffusion method [7]. The Gram-
Scheme 2. Synthesis of N-p-methoxybenzyl protected 3-bromo substituted 1,8-naphthyridin-2(1H)-ones.
I
Br
R1
Br
H N
Br
2
1
2
N
N
O
N
N
O
N
N
O
PMB
PMB
PMB
6
7
8
bꢀ8d
3
NH2
O
NH
Br
N
N
O
PMB
8a
R = CN (8b), m-OMeC H (8c), OEt (8d).
1
6 4
Reagents and conditions: (1) NaNO , con. HCl, –5°C, KI, H O; (2) dimethylformamide, Zn(CN) , Pd(PPh ) , 80°C,
2
2
2
3 4
3
-MeOC H B(OH) , Pd(PPh ) , 1,4-dioxane, H2O ,CuI, 1,10-phenanthroline, Cs CO , ethanol; (3) NaOCN, acetic
6 4 2 3 4 2 3
acid–water.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 12 2019

2536
SAKRAM et al.
Scheme 3. Synthesis of 3-anilino-1,8-naphthyridin-2(1H)-one derivatives 10a–10e.
R2
R2
R1
Br
O
R1
NH
R1
NH
1
2
N
N
N
N
H
N
N
PMB
9aꢀ9e
O
O
PMB
8
aꢀ8d
10aꢀ10e
R = NHCONH , CN, phenyl m-OCH , OCH CH ; R = H, NH–CO-pyrrolidine; PMB is 4-methoxybenzyl.
1
2
3
2
3
2
Reagents and conditions: aniline; (1) t-butyl alcohol, K CO , Pd (dba) , XPhos; (2) trifluoro methanesulfonic acid,
2
3
2
3
trifluoroacetic acid.
substituted 3-anilino1,8-naphthyridin-2(1H)-ones. The
compounds 9b–9d and 10b–10d were characterized by
the highest activity.
the product 9b could be involved in formation of three
hydrogen bonds with ARG194, THR212 and THR212,
and ARG194, THR212 and THR212 of PBP6 were in-
volved in π–π interaction with all ligands.
Molecular docking. The docking studies were carried
out using discovery studio software Cdocker algorithm
EXPERIMENTAL
[
8]. The crystallographic data of penicillin-binding
All solvents and reagents were purchased as analyti-
cal-grade from commercial sources and used without fur-
ther purification.All glassware used in moisture sensitive
reactions was oven dried. Melting points were recorded on
a Reichert “Thermopane” microscope hot stage apparatus
protein 6 (PBP6) of Escherichia coli (PDB: 3ITA) were
retrieved from Protein Data Bank. The docking study of
compounds 9b–9e and 10b–10e with PBP6 revealed the
high Cdocker energy (docking score), and binding affini-
ties were in the range of 36.406 to 45.219, as compared
to penicillin 49.421 (Table 2).
1
and are uncorrected. H NMR spectra were measured on
a Bruker AV-500 spectrometer using DMSO-d as a sol-
6
These results indicated that most of the compounds
were docked within the binding site pocket of penicillin.
The sample interactions of compound 9b with receptors
are illustrated below in the figure. According to docking
data the synthesized compounds could be characterized by
good binding interactions with the receptor. For example,
vent. Low-resolution electrospray ionization (ESI) mass
spectra were measured on a Bruker Daltronics Esquire
6
000 ion trap mass spectrometer at 300°C with a scan
rate of 5500 m/z/s, a 40 eV cone voltage and in positive
mode unless otherwise stated.
3
-Bromo-1-(4-methoxybenzyl)-6-nitro-1,8-naph-
thyridin-2(1H)-one (5). To a mixture of 3-bromo-6-
nitro-1,8-naphthyridin-2(1H)-one (4) (3.78 g, 14 mmol)
with 40 mL of anhydrous DMF, were added K CO3
2
(
(
2.86 g, 20 mmol) and p-methoxybenzyl chloride
2.98 mL, 21.03 mmol). The reaction was stirred at room
temperature for 5 h and then heated at 50°C overnight.
After completion of the reaction, according to TLC, the
mixture was poured onto ice. The precipitate formed was
filtered off, washed with H O and recrystallized from
2
EtOH to give the product 5 as a white solid, yield 91%.
6-Amino-3-bromo-1-(4-methoxybenzyl)-1,8-naph-
thyridin-2(1H)-one (6). To a mixture of compound 5
Interactions of compound 9b.
(1.17 g, 3mmol) in 60 mL of MeOH and 15 mL AcOH,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 12 2019

SYNTHESIS AND ANTIBACTERIAL ACTIVITY
2537
Table 1. Structures, yields and melting points of the synthesized compounds
Compound Structure
Yield, %
84
mp, °C
8
a
H
251–253
H N
N
Br
O
2
O
N
N
O
8
b
N
89
217–219
Br
O
N
N
O
8
c
85
76–78
Br
O
O
N
N
O
O
Br
O
8
d
79
82
132–134
314–316
N
N
O
9
a
H
H
H N
N
N
2
O
N
N
O
O
9
b
88
184–186
H
N
H
N
H
H N
N
N
2
O
O
N
N
O
O
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 12 2019

2538
SAKRAM et al.
Table 1. (Contd.)
9
c
N
H
N
H
N
93
85
220–223
121–123
N
O
N
N
O
O
9
d
H
N
H
N
N
O
O
N
N
O
O
9
e
H
H
84
215–217
O
N
N
N
O
N
N
O
O
1
0a
H
N
H
86
88
314–316
315–317
H N
N
2
O
N
N
O
H
1
0b
H
N
H
N
H
N
H N
N
2
O
O
N
N
O
H
1
0c
95
87
296–298
219–221
N
H
H
N
N
N
O
N
N
O
H
1
0d
H
H
N
N
N
O
O
N
N
H
O
1
0e
83
240-243
H
N
H
N
O
N
O
N
N
H
O
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 12 2019

SYNTHESIS AND ANTIBACTERIAL ACTIVITY
Table 2. The accumulated docking data for the selected compounds
2539
Van der
Waals
energy
Comp. Cdocker Electrostatic
Bond
distance
H
Interacting atoms
Donor Acceptor
no.
energy
energy
bonds no.
6
11
O6
9
b
43.341
–48.875
1.855
A:ARG194: HH11 (9b): O
2.133000 HH
1.922000 HG
2.424000 HN
3
1
4
1
14
A:THR212: HG1 (9b): O
O
O
1
4
14
A:THR212: HN (9b): O
9
9
c
36.406
45.219
–25.731
–23.399
1.912
5.995
A:SER40:HG (9c): O4
2.447000 HG
O4
1
2
1
1
2.203000 HG1
11
d
A:THR210:HG1 (9d): O
O
O
1
1
11
A:THR210:HN (9d): O
2.108000 HN
3
2
32
A:SER82:HA (9d): C
2.163000
C
HA
3
12
11
O3
OG
1
0b
0c
38.094
36.817
–55.357
–39.564
0,401
3.868
A:ARG194:HH12 (10b): O
(
2.495000 HH
2
2
3
7
37
1
10b): H –A:THR210: OG1 2.054000
H
A:ARG194:HE (10c): O9
A:ARG194:HH11 (10c): O
2.429000 HE
O
9
1
9
9
2.035000 HH
O
2
9
29
1
(
10c): C –A:SER83:HB1
2.141000
C
HB
1
0d
42.693
49.421
–39.521
–42.724
3.739
(10d): H45 – A:SER83:O
A:SER40:HG (10d): N
A:ARG194:HH10 (10d): O
2.450000 H45
2.334000 HG
2.293000 HH
O
3
3
11
11
N
O
2
8
11
28
4
O4
Penci
–1.677 A:ARG194:HE – Penci:O
2.088000 HE
3
4
34
1
Penci:H –A:THR210:OG1
2.073000
H
OG
5
5
A:SER40:HG – Penci:O
2.073000 HG
O
3
5
35
1
1
Penci:H –A:SER82:HB1
Penci:C –A:SER82:HB1
1.265000
2.181000
H
C
HB
HB
1
7
17
was added Zn powder (10 equiv) and the reaction mixture
was refluxed for 30 min (TLC). After completion of the
reaction, the excess Zn was filtered off and the filtrate was
concentrated in vacuo. The resulting residue was tritu-
rated with CH Cl , filtered again and the filtrate washed
2.5 M NaOH (2×50 mL), 10% Na S O (2×100 mL),
2 2 3
2.5 M NaOH (1×100 mL), H O (2×200 mL), and brine
2
(1×100 mL), dried, filtered and the solvent was evapo-
rated under vacuum to afford a light brown solid which
2
2
with saturated NaHCO (2×100 mL), brine (2×100 mL),
Table 3. In vitro antibacterial activity of the selected products
3
dried, filtered, and the solvent was removed in vacuo to
give a yellow solid which was purified by flash chroma-
tography (60% EtOAc–hexanes) and recrystallized from
i-PrOH to give product 6 as a white solid. Yield 78%.
MIC, μg/mL
Compound
E. coli
15.50
8.05
S.aureus
12.40
10.13
9.09
9
9
9
9
a
b
c
3
-Bromo-6-iodo-1-(4-methoxybenzyl)-1,8-naph-
thyridin-2(1H)-one (7). To a suspension of 6-amino-
-bromo-1-(4-methoxybenzyl)-1,8-naphthyridin-2(1H)-
8.52
3
d
8.63
9.25
one (6) (1.94 g, 5.40 mmol) in conc. HCl (60 mL) at –5°C,
was added NaNO (0.074g, 11 mmol) dissolved in H O
9e
12.30
13.15
8.19
13.08
14.50
9.21
2
2
(50 mL) dropwise over 10 min, and the reaction mixture
1
1
1
1
1
0a
was stirred for 1 h (TLC). After completion of the reac-
tion, the resulting yellow mixture was added dropwise
0b
0c
0d
0e
8.11
10.50
10.45
13.16
9.50
at –5°C to a solution of KI (50 equiv) in H O (250 mL)
2
and stirred for 15 min at –5°C, followed by stirring for
8.89
4
h at room temperature. After that the reaction mixture
11.20
8.20
was diluted with H O and extracted by EtOAc (3×100
2
Ciprofloxacin
mL). The combined organic extracts were washed with
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 12 2019

2540
SAKRAM et al.
was recrystallized from n-PrOH to give the product 7 as
7 (0.98g, 2.1 mmol) with Cs CO (0.52g, 1.6 mmol)
2 3
a light brown solid.
and 1,10-phenanthroline (0.40g, 20 mol %) in EtOH
40 mL), was added CuI (0.20g, 10 mol %). The mixture
(
1
-[6-Bromo-8-(4-methoxybenzyl)-7-oxo-7,8-di-
was heated to 110°C in a pressure tube for 16 h, after
which the reaction mixture was cooled down and passed
through a silica pad (eluent EtOAc). The collected frac-
tion was concentrated in vacuo to obtain the crude mixture
of the desired ethoxy derivative 8d in combination with
two other cross-coupled side-products. The mixture was
separated by flash chromatography (EtOAc–hexane) to
isolate product 8d as a brown solid.
hydro-1,8-naphthyridin-3-yl]urea (8a). To a solution
of 6-amino-3-bromo-1-(4-methoxybenzyl)-1,8-naphthy-
ridin-2(1H)-one (6) (1.04 g, 2.90mml) inAcOH (30 mL)
was added a solution of NaOCN (0.40 g, 6.30 mmol) in
H O (10 mL), and the reaction mixture was refluxed at
2
room temperature for 60 min (TLC). After completion
of the reaction the mixture was poured onto ice and the
precipitated solid was filtered off and washed with H O,
2
then recrystallized from cyclohexanone–n-PrOH to give
product 8a as a white solid.
Synthesis of 1-[8-(4-methoxybenzyl)-7-oxo-6-
(phenylamino)-7,8-dihydro-1,8-naphthyridin-3-yl]-
urea (9a–9e). To a mixture of bromo substituted
6
-Bromo-8-(4-methoxybenzyl)-7-oxo-7,8-di-
1
,8-naphthyridine-2(1H)-one 8a (2 mmol) with aniline
hydro-1,8-naphthyridine-3-carbonitrile (8b). To a
solution of compound 7 (0.94 g, 2mmol) in DMF (10 mL)
(
(
1 mmol) and K CO (1.5 mmol) in anhydrous t-BuOH
40 mL) purged with argon were added XPhos (10 mol %)
2
3
was added Zn(CN) (0.046 g, 0.40mmol), and the mix-
2
and Pd (dba) (5 mol %), and the reaction mixture was
ture was purged with argon. Upon addition of Pd(PPh3)4
2
3
refluxed for 16 h (TL). After completion of the pro-
cess, the mixture was cooled down to room tempera-
ture, treated with H O and extracted with CH Cl (2×
(
0.60g, 6.8mml) the reaction mixture was heated to 90°C
for 4 h (TLC), then it was cooled down, diluted with
0% NH OH and extracted with EtOAc (2×100 mL).
2
2
2
3
4
1
00 mL). The combined organic extracts were washed
The combined organic extracts were washed with brine
2×100 mL), dried, filtered, and the solvent was removed
with brine (1×100 mL), dried, and filtered, and the
solvent was removed in vacuo to give a dark red resi-
due. The residue was purified by flash chromatography
(
under vacuum to give a yellow solid which was purified
by flash chromatography (0–2% MeOH/CH Cl ) and
2
2
(
MeOH–CH Cl ) and recrystallized from n-PrOH to give
2 2
recrystallized from n-PrOH to give the product 8b as a
white solid.
N-PMB protected 1,8-naphthyridine-2(1H)-one 9a as a
white solid.
3
-Bromo-1-(4-methoxybenzyl)-6-(3-methoxy-
Compounds 9b–9e were synthesized as described in
the above procedure for 9a.
phenyl)-1,8-naphthyridin-2(1H)-one (8c). To a solution
of compound 7 (0.50g, 1.3 mmol) in 1,4-dioxane (20 mL)
Synthesis of 3-anilino1,8-naphthyridin-2(1H)-ones
and H O (2 mL) were added 3-methoxyphenyl boronic
2
10a–10e. To a solution of N-PMB protected 1,8-naphthy-
acid (1.2 equiv), Na CO (0.20g, 1.9 mmol) and LiCl
2
3
ridin-2(1H)-one 9a (0.80g, 1mmol) in TFA (5 mL) was
added TfOH (3 equiv). The reaction mixture was stirred
at room temperature for 3 h and then carefully poured
(
0.78g, 1.8 mmol), and purged with argon. To the above
mixture was added Pd(PPh ) (40mg, 5 mol %), and the
3
4
reaction mixture was heated to 90°C overnight (TLC),
then it was cooled down and the solvent was evaporated
under vacuum. The residue was dissolved in CH Cl ,
onto ice-cold saturated solution of NaHCO . The solid
3
residue was separated, filtered off and then extracted with
2
2
CH Cl (3×50 mL). The combined organic extracts were
washed with H O (2×100 mL), brine (2×100 mL), dried,
2
2
2
washed with brine (2×100 mL), dried, and filtered, and
the solvent was removed in vacuo to give a light brown
solid. The resulting crude solid was combined with the
previously isolated solid and purified by flash chromatog-
filtered, and the solvent was removed in vacuo to afford
a brown residue, which was purified by flash chroma-
tography (15–20% EtOAc–hexane) to afford a mixture
of compounds 8c and bis(3-methoxyphenyl) substituted
side product (10 : 1) obtained as a light brown residue.
The impurity was removed by flash chromatography (10%
EtOAc–hexane) and the pure product 8c was isolated as
a light yellow solid.
raphy (MeOH–CH Cl saturated with NH ) followed by
2
2
3
recrystallization from EtOH to afford the compound 10a.
Compounds 10b–10e were synthesized as described
in the above procedure for 10a.
3
-Bromo-6-ethoxy-1-(4-methoxybenzyl)-1,8-naph-
3-Bromo-1-(4-methoxybenzyl)-6-nitro-1,8-
naphthyridin-2(1H)-one (5). White solid, mp 223–
thyridin-2(1H)-one (8d). To a suspension of compound
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 12 2019

SYNTHESIS AND ANTIBACTERIAL ACTIVITY
2541
1
2
(
25°C. H NMR spectrum, δ, ppm: 3.79 s (3H), 5.41 s
3-Bromo-6-ethoxy-1-(4-methoxybenzyl)-1,8-naph-
thyridin-2(1H)-one (8d). Brown solid. Н NMR spec-
1
2H), 6.91 d (2H, J = 7.8 Hz), 7.27 s (1H), 7.36 d (2H, J =
7
.8 Hz), 8.98 d (1H, J = 1.5 Hz), 9.20 d (1H, J = 1.5 Hz).
trum, δ, ppm: 1.38 t (3H, J = 6.5 Hz), 3.70 s (3H), 4.03 q.t
(2H, J = 6.5 Hz), 5.41 s (2H), 6.89 d (2H, J = 9.0 Hz),
7.15 s (2H, J = 9.0 Hz), 7.63 s (1H), 7.71 s (1H, J =
+
MS (ESI): m/z: 390.23 [M + H] . Found, %: C 49.25; H
3
.10; N 10.77. C H BrN O . Calculated, %: C 49.34;
16 12 3 4
H 3.23; N 10.88.
2.5 Hz), 7.95 s (1H, J = 2.5 Hz). MS (ESI): m/z: 389.15
+
[
M + H] . Found, %: C 55.39; H 4.23; N 7.08.
6-Amino-3-bromo-1-(4-methoxybenzyl)-1,8-naph-
C H BrN O . Calculated, %: C 55.54; H 4.40; N 7.20.
1
18 17
2
3
thyridin-2(1H)-one (6). White solid, mp 183–185°C. Н
NMR spectrum, δ, ppm: 3.69 s ( 3H), 5.06 s (2H), 5.49
s (2H), 6.96 d (2H, J = 8.0Hz), 7.11 d (1H, J = 2.0 Hz),
N-[8-(4-Methoxybenzyl)-7-oxo-6-(phenylamino)-
7
,8-dihydro-1,8-naphthyridin-3-yl]urea (9a). White
1
solid. Н NMR spectrum, δ, ppm: 3.78 s (3H), 5.35 s
7.39 s (2H, J = 8.0Hz), 7.58 s (1H), 7.89 d (1H, J = 2.0Hz.
(2H), 5.81 s (2H), 6.38 s (1H), 6.69–6.73 m (3H), 6.89 d
Found, %: C 53.35; H 3.92; N 11.67. C H BrN O .
Calculated, %: C 53.45; H 3.98; N 11.76.
1
6
14
3
2
(2H, J = 8.5 Hz), 7.20 t (2H, J = 8.0 Hz), 7.41 d (2H, J =
8
9
.5 Hz), 7.79 d (1H, J = 2.0 Hz), 8.20 d (1H, J = 2.0 Hz),
3
-Bromo-6-iodo-1-(4-methoxybenzyl)-1,8-naph-
.10 s (1H), 9.81 s (1H). MS (ESI): m/z: 416.05 [M +
thyridin-2(1H)-one (7). Light brown solid, mp 215–
+
H] . Found, %: C 66.31; H 5.01; N 16.48. C H N O .
1
23 21
5
3
2
17°C. Н NMR spectrum, δ, ppm: 3.76 s (3H), 5.38 s
Calculated, %: C 66.49; H 5.10; N 16.86.
(2H), 6.94 d (2H, J = 9.0Hz), 7.21 s (1H), 7.33 d (2H, J =
N-(3-{[1-(4-Methoxybenzyl)-2-oxo-6-ureido-1,2-
9
.0 Hz), 8.19 d (1H, J = 1.5 Hz), 8.78 d (1H, J = 1.5Hz).
dihydro-1,8-naphthyridin-3-yl]amino}phenyl)pyr-
+
MS (ESI): m/z: 470.18 [M + H] . Found, %: C 40.54; H
1
rolidine-1-carboxamide (9b). White solid. Н NMR
2
.37; N 5.76. C H BrIN O . Calculated, %: C 40.79;
16 12 2 2
spectrum, δ, ppm: 1.82–1.86 m (4H), 3.37–3.40 m (4H),
H 2.57; N 5.95.
3
8
.68 s (3H), 5.56 s (2H), 5.83 s (2H), 6.24 d.t (1H, J =
.0 Hz, J = 1.5 Hz ), 6.40 s (1H), 6.58 s (1H), 6.87 d (2H,
1
-[6-Bromo-8-(4-methoxybenzyl)-7-oxo-7,8-di-
hydro-1,8-naphthyridin-3-yl]urea (8a). White solid.
1Н NMR spectrum, δ, ppm 3.78 s (3H), 5.48 s (2H), 5.89
s (2H), 6.87 d (2H, J = 9.0 Hz), 7.38 d (2H, J = 9.0 Hz),
J = 8.5 Hz), 7.03 d.t (1H, J = 8.0 Hz, J = 1.5 Hz), 7.20 t
1H, J = 7.5 Hz), 7.38 d (2H, J = 8.5 Hz), 7.88 d (1H, J =
(
1
9
.5 Hz), 8.04 d (1H, J = 1.5 Hz), 8.70 s (1H), 9.35 s (1H),
.84 s (1H). MS (ESI): m/z: 528.18 [M + H] . Found, %:
7
1
.58 s (1H), 7.99 d (1H, J = 1.5 Hz), 8.64 d (1H, J =
.5 Hz), 9.30 s (1H). MS (ESI): m/z: 403.18 [M + H]+.
+
C 63.74; H 5.54; N 18.58. C H N O . Calculated, %:
2
8
29
7
4
Found, %: C 50.64; H 3.75; N 13.89. C H BrN O .
Calculated, %: C 50.75; H 3.86; N 13.96.
1
7
15
4
3
C 63.56; H 5.38; N 18.45.
N-(3-{[6-Cyano-1-(4-methoxybenzyl)-2-oxo-
6
-Bromo-8-(4-methoxybenzyl)-7-oxo-7,8-di-
1
,2-dihydro-1,8-naphthyridin-3-yl]amino}phenyl)
hydro-1,8-naphthyridine-3-carbonitrile (8b). White
1
pyrrolidine-1-carboxamide (9c). Light yellow solid. Н
NMR spectrum, δ, ppm: 1.83–1.85 m (4H), 3.36–3.40 m
1
solid. Н NMR spectrum, δ, ppm: 3.77 s (3H), 5.43 s (2H),
6
.87 d (2H, J = 8.5 Hz), 7.20 d (2H, J = 8.5 Hz), 7.97 s
(4H), 3.80 s (3H), 5.58 s (2H), 6.27 d (1H, J = 9.0 Hz),
(1H), 8.43 d (1H, J = 2.0 Hz), 8.90 d (1H, J = 2.0 Hz).
6
.40 s (1H), 6.68 t (1H, J = 1.5 Hz), 6.95d (2H, J = 9.0
+
MS (ESI): m/z: 370.18 [M + H] . Found, %: C 55.04; H
Hz), 7.10 d.d (1H, J = 7.8 Hz, J = 1.0 Hz), 7.21 t (1H,
J = 7.8Hz), 7.36 d (2H, J = 9.0 Hz), 8.20 s (1H, J = 1.6
Hz), 8.34 s (1H, J = 1.6 Hz), 9.21 s (1H), 9.45 s (1H).
3
.18; N 11.21. C H BrN O . Calculated, %: C 55.15;
17 12 3 2
H 3.27; N 11.35.
+
3
-Bromo-1-(4-methoxybenzyl)-6-(3-meth-
MS (ESI): m/z: 495.11 [M + H] . Found, %: C 66.78; H
oxyphenyl)-1,8-naphthyridin-2(1H)-one (8c). Light
5.16; N 16.75. C28H26N6O3. Calculated, %: C 68.00; H
5.30; N 16.99.
1
yellow solid. Н NMR spectrum, δ, ppm: 3.70 s (3H),
.83 s (3H), 5.21 s (2H), 6.88 d (2H, J = 8.0 Hz), 7.01 d.t
1H, J = 8.0 Hz, J = 1.5 Hz), 7.14–7.21 m (2H), 7.39 s (2H,
J = 8.0 Hz), 7.54 t (1H, J = 7.5 Hz), 7.71 s (1H), 8.14 s
3
(
N-(3-{[1-(4-Methoxybenzyl)-6-(3-methoxyphenyl)-
2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]amino}phe-
1
nyl)pyrrolidine-1-carboxamide (9d). White solid. Н
(
4
1H, J = 2.0 Hz), 8.60 s (1H, J = 2.0 Hz). MS (ESI): m/z:
51.28 [M + H] . Found, %: C 61.08; H 4.13; Br, 17.56;
NMR spectrum, δ, ppm: 1.94–1.98 m (4H), 3.36–3.40 m
(4H), 3.67 s (3H), 3.78 s (3H), 5.24 s (2H), 6.37 d.t (1H, J =
7.8 Hz, J = 1.4 Hz), 6.48 s (1H), 6.60 t (1H, J = 1.5 Hz),
6.95–6.98 m (3H), 7.24–7.30 m (4H), 7.39 d.d (3H, J =
+
N 6.10. C H BrN O . Calculated, %: C 61.21; H 4.24;
Br, 17.70; N 6.21.
23
19
2
3
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 12 2019

2542
SAKRAM et al.
8
.0 Hz, J = 6.5 Hz), 7.97 d (1H, J = 2.0Hz), 8.19 d (1H,
Hz, J = 2.0 Hz), 7.46 d (1H, J = 8.0 Hz), 8.05 d (1H, J =
2.0 Hz), 8.20 d (1H, J = 2.0 Hz), 8.89 s (1H), 9.42 s (1H),
12.24 s (1H). MS (ESI): m/z: 456.04 [M + H] . Found,
J = 2.0 Hz), 8.75 s (1H), 9.78 s (1H). MS (ESI): m/z:
+
+
5
76.06 [M + H] . Found, %: C 70.61; H 5.40; N 12.03.
C H N O . Calculated, %: C 70.94; H 5.78; N 12.17.
%: C 68.56; H 5.53; N 15.37. C H N O . Calculated,
34
33
5
4
26 25
5
3
%: C 68.38; H 5.34; N 15.19.
N-(3-{[6-Ethoxy-1-(4-methoxybenzyl)-2-oxo-
1
,2-dihydro-1,8-naphthyridin-3-yl]amino}phenyl)-
N-{3-[(6-Ethoxy-2-oxo-1,2-dihydro-1,8-naphthy-
1
pyrrolidine-1-carboxamide(9e). Yellow solid. Н NMR
spectrum, δ, ppm:1.30t(3H, J=6.8Hz), 1.80–1.84m(4H),
ridin-3-yl)amino]phenyl}pyrrolidine-1-carboxamide
1
(10e). White solid. Н NMR spectrum, δ, ppm: 1.30 t
3
5
6
.37–3.40 m (4H), 3.71 s (3H), 4.02 q (2H, J = 6.8 Hz),
.50s(2H), 6.30s(1H), 6.48d.t(1H, J=7.8Hz, J=1.5Hz),
.92–6.96 m (3H), 7.18 t (1H, J = 7.5Hz), 7.35–7.39 m
(3H, J = 7.0 Hz), 1.83–1.85 m (4H), 3.34–3.38 m (4H),
4.03 q (2H, J = 7.0 Hz), 6.37 s (1H), 6.64 d.t (1H, J =
8.0 Hz, J = 1.5 Hz), 6.76 t (1H, J = 1.5 Hz), 7.12 d.t (1H,
J = 8.0 Hz, J = 1.5 Hz), 7.33 d (1H, J = 8.0 Hz), 7.59 d
(1H, J = 1.6 Hz), 7.86 d (1H, J = 1.6 Hz), 8.73 s (1H),
9.87 s (1H), 12.08 s (1H). MS (ESI): m/z: 394.09 [M +
(4H), 7.96 d (1H, J = 1.6 Hz), 8.94 s (1H), 9.75 s (1H).
+
MS (ESI): m/z: 514.04 [M + H] . Found, %: C 67.64; H
5
.87; N 13.42. C H N O . Calculated, %: C 67.82; H
29 31 5 4
6
.08; N 13.64.
+
H] . Found, %: C 64.11; H 5.89; N 17.80. C H N O .
2
1
23
5
3
1
-[7-Oxo-6-(phenylamino)-7,8-dihydro-1,8-
Calculated, %: C 63.88; H 5.65; N 17.53.
CONCLUSIONS
1
naphthyridin-3-yl]urea (10a). White solid. Н NMR
spectrum, δ, ppm: 5.84 s (2H), 6.43 s (1H), 6.64 t (2H, J
=
8.0Hz), 7.09 tt (1H, J = 7.0Hz, J = 1.0Hz), 7.30 t d (2H,
An efficient synthetic approach to novel 3-N sub-
stituted 1,8-naphthyridin-2(1H)-ones. Application of
Buchwald-Hartwig cross-coupling has been found to be
more efficient than the conventional approach. Applica-
tion of the PMB protecting group provides leads to the
synthesis of different N-substituted 3-anilino1,8-naph-
thyridin-2(1H)-ones. The molecular docking procedure
has denoted probability of interactions of the synthesized
compounds 9b–9d and 10b–10d with penicillin-binding
protein 6. Preliminary studies indicate high antibacterial
activity of compounds 9b–9d and 10b–10d.
J = 8.0Hz), 7.69 d (1H, J = 2.0Hz), 7.93 d (1H, J = 2.0Hz),
8
2
.42 s (1H), 9.30 s (1H), 11.24 s (1H). MS (ESI): m/z:
96.04 [M + H] . Found, %: C 60.89; H 4.38; N 23.60.
+
C H N O . Calculated, %: C 61.01; H 4.44; N 23.72.
15
13
5
2
N-{3-[(2-Oxo-6-ureido-1,2-dihydro-1,8-naphthy-
ridin-3-yl)amino]phenyl}pyrrolidine-1-carboxamid
1
(10b).Whitesolid. НNMRspectrum,δ,ppm:1.90–1.94m
(4H), 3.30–3.39 m (4H), 6.34 s (1H), 6.49 d.t (1H, J =
8
7
9
.5 Hz, J = 1.5 Hz), 6.69 s (2H), 6.85 t (1H, J = 1.5 Hz),
.29–7.34 m (2H), 7.71 d (1H, J = 2.0 Hz), 8.21 s (1H),
.80 s (1H), 12.08 s (1H). MS (ESI): m/z: 408.08 [M +
+
FUNDING
H] . Found, %: C 58.96; H 5.20; N 24.07. Calculated,
%
: C 58.74; H 5.10; N 23.89.
One of the KurumannaAauthors would like to thank UGC
for research leading to these results has received from SRF-
fellowship providing for us, and also thank CFRD-OU for
analytical support.
N-{3-[(6-Cyano-2-oxo-1,2-dihydro-1,8-naphthy-
ridin-3-yl)amino]phenyl}pyrrolidine-1-carboxamide
1
(10c). Light yellow solid. Н NMR spectrum, δ, ppm:
1
6
.72–1.76 m (4H), 3.32–3.36 m (4H), 6.50 s (1H),
.68–6.74 m (1H), 6.96 t (1H, J = 1.4 Hz), 7.20–7.28 m
CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
REFERENCES
(2H), 8.21 d (1H, J = 1.5 Hz), 8.49 d (1H, J = 1.5 Hz),
8
3
.96 s (1H), 9.32 s (1H), 12.48 s (1H). MS (ESI): m/z:
75.08 [M + H] . Found, %: C 64.16; H 4.85; N 22.45.
+
C H N O . Calculated, %: C 63.88; H 4.64; N 22.38.
20
18
6
2
1
2
. Appelbaum, P.C. and Hunter, P.A., Int. J. Antimicrob.
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hydro-1,8-naphthyridin-3-yl]amino}phenyl)pyrro-
1
lidine-1-carboxamide (10d). White solid. Н NMR
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3
1
.74 s (3H), 6.35 s (1H), 6.53 d.t (1H, J = 7.8 Hz, J =
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 12 2019

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