A Simple “Green” Synthesis of Novel Bis(3-aryl-1,8-naphthyridin-2-yl)sulfanes and 2-(Methylthio)-3-aryl-1,8-naphthyridines under Microwave Irradiation and Conventional Conditions

Article abstract of DOI:10.1134/S1070363218060312

An eco-friendly and highly efficient synthesis of substituted bis(3-aryl-1,8-naphthyridin-2-yl)-sulfanes and 2-(methylthio)-3-aryl-1,8-naphthyridines under microwave and conventional conditions. The products are obtained with high yields and purity within short reaction time. The synthesized derivatives are screened for anti-microbial activity against bacteria and fungi. Molecular docking of the synthesized compounds with DNA Gyrase is studied.

Full text of DOI:10.1134/S1070363218060312

ISSN 1070-3632, Russian Journal of General Chemistry, 2018, Vol. 88, No. 6, pp. 1232–1237. © Pleiades Publishing, Ltd., 2018.
A Simple “Green” Synthesis
of Novel Bis(3-aryl-1,8-naphthyridin-2-yl)sulfanes
and 2-(Methylthio)-3-aryl-1,8-naphthyridines
under Microwave Irradiation and Conventional Conditions1
D. Ravia, K. Ashoka, S. Rambabua, B. Sakrama*, and P. Shyamb
a Department of Chemistry, Osmania University, Hyderabad, Telangana State, 500007 India
*e-mail: bschemou@gmail.com
b Biomedical Informatics Center, National Institute of Nutrition, Tarnaka, Hyderabad, 500007 India
Received April 2, 2018
Abstract—An eco-friendly and highly efficient synthesis of substituted bis(3-aryl-1,8-naphthyridin-2-yl)-
sulfanes and 2-(methylthio)-3-aryl-1,8-naphthyridines under microwave and conventional conditions. The
products are obtained with high yields and purity within short reaction time. The synthesized derivatives are
screened for anti-microbial activity against bacteria and fungi. Molecular docking of the synthesized
compounds with DNA Gyrase is studied.
Keywords: 1,8-naphthyridines, anti-microbial activity, methanol, microwave Irradiation, molecular docking
DOI: 10.1134/S1070363218060312
INTRODUCTION
naphthyridine-2-thiols (6) were accumulated in good
yields (Table 1). The structures of compounds were
confirmed on the basis of spectral data.
The reaction of 6 with sulfuric acid in methanol
under solvent-free conditions in 15–20 min gave 2-(methyl-
thio)-3-aryl-1,8-naphthyridines (7) in high yields
(Scheme 2, Table 2).
Nitrogen-containing heterocyclic compounds annealed
with 1,8-naphthyridine derivatives are attractive objects
of study due to their broad spectrum of biological
activities [1–3].
In continuation of our studies of solvent-free organic
reactions and eco-friendly methods [4, 5], we
developed the synthetic approaches to new di(3-aryl-
1,8-naphthyridin-2-yl)thioethers and 2-(methylthio)-3-
aryl-1,8-naphthyridines, that were characterized by
short reaction time and high yields.
A number of acids was tested in the process (Table 2)
and sulfuric acid was determined to be the most efficient.
EXPERIMENTAL
All reagents and solvents were purchased from
Merck/Aldrich and used without further purification.
Melting points were measured in open capillary tubes
in a Cintex apparatus. Purity of compounds was tested
by TLC on Merk plates, F254, and visualized under UV
light or iodine vapors. IR spectra were recorded on a
Perkin-Elmer spectrum BX series spectrophotometer
using KBr discs. 1H NMR spectra were measured on a
Bruker 400-MHz spectrometer using DMSO-d6 as a
solvent and TMS as an internal standard. EI-MS
spectra were measured on a Jeol JMSD-400 spectro-
meter at 70 eV. Microanalyses were performed on a
Perkin-Elmer 240 CHN elemental analyzer. Irradiation
was carried out in a domestic microwave oven.
RESULTS AND DISCUSSION
In the current study, pyridine-based substituted
2-chloro-3-aryl-1,8-naphthyridines (3) could be used
as suitable intermediates for the synthesis of the target
compounds. The compounds 3 could be synthesized in
high yields by interaction of the compounds 1, 2 with
POCl3 [6, 7] (Schemes 1, 2).
The following reaction with thiourea was carried
out under microwave irradiation or under conventional
conditions. In both cases the respective 3-aryl-1,8-
1 The text was submitted by the authors in English.
1232

A SIMPLE “GREEN” SYNTHESIS OF NOVEL BIS(3-ARYL-1,8-NAPHTHYRIDIN-2-YL)SULFANES
1233
Scheme 1. Synthesis of 3-aryl-1,8-naphthyridine-2-thiols and bis(3-aryl-1,8-naphthyridin-2-yl)sulfanes.
R
R
S
POCl3
+
H2N
NH2
N
N
R1
N
N
Cl
1a−1f (R1 = NH2)
2a−2f (R1 = OH)
4
3a−3f
2 : 1
1 : 1
Ethanol A/B
Ethanol A/B
R
R
N
N
N
S
N
N
SH
N
R
6a−6f
5a−5f
R = H (1a–3a, 5a, 6a), 2-CF3 (1b–3b, 5b, 6b), 4-OCH3 (1c–3c, 5c, 6c), 4-F (1d–3d, 5d, 6d), 4-NO2 (1e–3e, 5e, 6e), 2-OPh
(1f–3f, 5f, 6f); A is microwave method, 6–8 min; B is conventional method, reflux, 55–60 min.
Scheme 2. Synthesis of 2-(methylthio)-3-aryl-1,8-naphthyridines.
R
R
HO−CH3, H2SO4
Solvent-free,
CH3
15−20 min
N
N
SH
N
N
S
6a−6f
7a−7f
R = H (6a, 7a), o-CF3 (6b, 7b), p-OCH3 (6c, 7c), p-F (6d, 7d), p-NO2 (6e, 7e), o-OPh (6f, 7f).
Synthesis of 3-aryl-1,8-naphthyridin-2-ol (2a–2f).
was dissolved in cold water and saturated NaHCO3.
The organic phase was evaporated. The crude product
was filtered off, washed with water and recrystallized
from methanol.
To a solution of (1 mmol, 1a–1f) in 2 N HCl (10 mL)
was added NaNO2 solution (1 mmol in 10 mL of
water) and the reaction mixture was stirred at room
temperature for 35 min, then treated with cold water.
The solid thus obtained was filtered off, washed with
water and recrystallized from ethanol.
Synthesis of bis(3-aryl-1,8-naphthyridin-2-yl)sulfanes
(5a–5f). Method A: microwave conditions. the mixture
of 2-chloro-3-aryl-1,8-naphthyridines 3a–3f (0.2 mmol)
with thiourea (0.1 mmol, 4 mL), and ethanol (1.5 mL)
was exposed to microwave irradiation at 200 W with
pulses of 30 s, and gaps of 15 s for 6.0 to 8.0 min upon
TLC monitoring. The reaction mixture was cooled
Synthesis of 2-chloro-3-phenyl-1,8-naphthyridine
(3a–3f). A solution of a compounds 2a–2f (1 mmol)
with POCl3 (15 mL) was heated for 6 h. Upon cooling
down to room temperature, the resulting reaction mixture
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RAVI et al.
Table 1. Yields and reaction time for synthesis of C3 substituted 1,8-naphthyridine derivatives
Microwave
time, min
Heating
Analog
R
mp, °C
yielda, %
time, min
yielda, %
5a
5b
5c
5d
5e
5f
H
8
6
7
6
6
8
69
78
67
65
74
70
55
58
55
60
50
60
52
56
60
55
61
59
220–222
233–235
228–230
216–218
230–232
236–238
o-CF3
p-OCH3
p-F
p-NO2
o-OPh
a Yields refer to pure isolated products.
down to room temperature and treated with 2% NaOH.
The solid product thus obtained was recrystallized
from ethanol.
spectrum, δ, ppm: 7.28 s (2H, ArH), 7.39–7.48 m (6H,
ArH), 7.74 d (J = 6.7 Hz, 4H, ArH), 8.12–8.21 m (4H,
ArH), 8.52 s (2H, ArH). LCMS: m/z: 443 [М + Н]+.
Found, %: C 76.11; H 4.19; N 12.51. C28H18N4S.
Calculated, %: C 75.99; H 4.10; N 12.66.
Method B: conventional conditions. A mixture of
2 mmol of a compounds 3a–3f with 1 mmol of thio-
urea in ethanol (15 mL) was refluxed for 50–60 min
(Table 1). Upon completion of the reaction (TLC), the
mixture was cooled down and treated with 2% NaOH.
The corresponding product was filtered off, washed
with water and recrystallized from methanol.
Bis{3-[2-(trifluoromethyl)phenyl]-1,8-naphthyridin-
2-yl}sulfane (5b). Off white solid. FT–IR spectrum, ν,
cm–1: 3030 (Ar–CH), 1666 (C=N), 1566 (C=C), 1271–
1010 (C–F), 711 (C–S–C). 1H NMR spectrum, δ, ppm:
7.26–7.31 m (2H, ArH), 7.52 d (J = 8.5 Hz, 4H, ArH),
7.80 d (J = 8.5 Hz, 4H, ArH), 8.15–8.21 m (4H, ArH),
8.53 d (J = 4.5 Hz, 2H, ArH). LCMS: m/z: 579 [М +
Н]+. Found: C 62.12; H 2.81; N 9.52. C30H16F6N4S.
Calculated %: C 62.28; H 2.79; N 9.68.
Synthesis of 3-aryl-1,8-naphthyridine-2-thiols (6a–
6f). A mixture of 0.1 mmol of a compounds 3a–3f with
0.1 mmol of thiourea in ethanol (1.5 mL) was MW
irradiated in an oven at 350 W for 3.0–4.0 min (2 + 2
with an intermission of 4 min). Upon completion, the
reaction mixture was cooled down and treated with 2%
NaOH. The corresponding product was filtered off,
washed with water and recrystallized from methanol.
Bis[3-(4-methoxyphenyl)-1,8-naphthyridin-2-yl]-
sulfane (5c). Yellow solid. FT–IR spectrum, ν, cm–1:
3080 (Ar–CH), 1672 (C=N), 1581 (C=C), 1251 (C–O),
1
719 (C–S–C). H NMR spectrum, δ, ppm: 3.81 s (6H,
2-OCH3), 7.08 d (J = 8.7 Hz, 4H, ArH), 7.19 d (J =
7.7 Hz, 2H, ArH), 7.44–7.49 m (4H, ArH), 7.84 s (2H,
ArH), 8.10 d (J = 7.7 Hz, 2H, ArH), 8.70 d (J =
4.5 Hz, 2H, ArH). LCMS, m/z: 503 [М + Н]+. Found,
Bis(3-phenyl-1,8-naphthyridin-2-yl)sulfane (5a).
White solid. FT–IR spectrum, ν, cm–1: 3034 (Ar–CH),
1
1654 (C=N), 1566 (C=C), 696 (C–S–C). H NMR
Table 2. Methylation of 3-phenyl-1,8-naphthyridine-2-thiol
(6a) with acidic methanola
Table 3. Methylation of 3-aryl-1,8-naphthyridine-2-thiols
6b–6f with acidic methanola
Thiol
6b
Product
7b
Time, min
Yieldb, %
Acid
Equivalent
Yield of 7a, %
20
20
15
15
20
68
71
65
69
60
H2SO4
3.0
1.5
1.5
2.0
2.5
70
57
6c
7c
p-TsOH·H2O
BF3·OEt2
HClaq
6d
7d
61
6e
7e
56
6f
7f
AcOH
Ttraces
a Thiol 1.0 mmol, H2SO4 0.2 mL, MeOH 5.0 mL, solvent-free.
a 6a 1.0 mmol, MeOH 5.0 mL, solvent-free, 15 min.
b Isolated product.
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A SIMPLE “GREEN” SYNTHESIS OF NOVEL BIS(3-ARYL-1,8-NAPHTHYRIDIN-2-YL)SULFANES
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Table 4. Antimicrobial activity data of the synthesized compounds 5a–5f and 7a–7f at two different concentrations (50 and
1000 μg/mL)a
Zone of inhibition, %
antibacterial activity
antifungal activity
Compound
Escherichia coli Staphylococcus aureus
Aspergillus Niger
Helmenthosphorium oryzae
100
5
50
100
6
50
4
5
6
5
4
6
3
4
6
5
4
3
8
–
100
6
50
100
7
50
3
5a
5b
5c
5d
5e
5f
3
4
5
4
4
9
9
8.5
9
5
9
5
10
8
10
7
6
10
7
6
8
4
5
7
3.5
4.5
3
8
8
4
8
4
9.5
4
9.5
7
10
6
5.5
3
9.5
7
6
7a
7b
7c
7d
7e
7f
4
8
4
7
7
3.5
5.5
5
8
4
9
4.5
3.5
3
9
10
7
0.9
7.5
7
6
8
7
5.5
4
8
6
6
3.5
2
7
4
5
5
5
3
Pencillin
12
–
7
11
–
–
–
–
–
Griseofulvin
–
11
8
13
08
a The bold values indicate the compounds of the highest antimicrobial activity.
%: C 71.62; H 4.22; N 10.96. C30H22N4O2S. Calculated,
Bis[3-(2-phenoxyphenyl)-1,8-naphthyridin-2-yl]-
%: C 71.69; H 4.41; N 11.15.
sulfane (5f). Brown solid. FT–IR spectrum, ν, cm–1:
3059 (Ar–CH), 1670 (C=N), 1581 (C=C), 1251, 1197
1
Bis[3-(4-fluorophenyl)-1,8-naphthyridin-2-yl]-
sulfane (5d). White solid. FT–IR spectrum, ν, cm–1:
3070 (Ar–CH), 1666 (C=N), 1579 (C=C), 1350-1201
(C–F), 719 (C–S–C). 1H NMR spectrum, δ, ppm: 7.25–
7.32 m (3H, ArH), 7.38–7.48 m (2H, ArH), 7.68–7.78
m (3H, ArH), 7.87–7.95 m (2H, ArH), 8.11–8.19 m
(1H, ArH), 8.44–8.58 m (5H, ArH). LCMS, m/z: 479
[М + Н]+. Found, %: C 70.15; H 3.24; N 11.85.
C28H16F2N4S. Calculated, %: C 70.28; H 3.37; N 11.71.
(C–O–C), 721 (C–S–C). H NMR spectrum, δ, ppm:
7.21 d (J = 7.7 Hz, 1H, ArH), 7.37–7.44 m (5H, ArH),
7.57 d (J = 4.0 Hz, 3H, ArH), 7.72–7.78 m (5H, ArH),
7.91 s (1H, ArH), 8.10–8.23 m (5H, ArH), 8.52–8.58
m (4H, ArH), 8.70–8.75 m (2H, ArH). LCMS, m/z:
627 [М + Н]+. Found, %: C 76.51; H 4.19; N 9.05.
C40H26N4O2S. Calculated, %: C 76.66; H 4.18; N 8.94.
Synthesis of 2-(methylthio)-3-aryl-1,8-naphthyri-
dines (7a–7f) (general procedure). To a solution of
3-aryl-1,8-naphthyridine-2-thiols (6a–6f) (1.0 mmol)
in Me-OH (5.0 mL) was added H2SO4 (0.2 mL), and
the mixture was stored for 15-20 min. On completion
of the process (TLC), the reaction mixture was poured
into cold water. The solid product was filtered off,
washed with water and recrystallized from methanol.
Bis[3-(4-nitrophenyl)-1,8-naphthyridin-2-yl]-
sulfane (5e). Pale yellow solid. FT–IR spectrum, ν, cm–1:
3107 (Ar–CH), 1656 (C=N), 1579 (C=C), 1346 (N–O),
696 (C–S–C). 1H NMR spectrum, δ, ppm: 7.23–7.37 m
(6H, ArH), 7.75–7.84 m (4H, ArH), 8.09–8.23 m (4H,
ArH), 8.51–8.60 m (2H, ArH). LCMS, m/z: 533 [М +
Н]+. Found, %: C 63.20; H 3.00; N 15.85.
C28H16N6O4S. Calculated, %: C 63.15; H 3.03; N 15.78.
2-(Methylthio)-3-phenyl-1,8-naphthyridine (7a).
Off white solid, mp 190–192°C. FT–IR spectrum, ν,
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RAVI et al.
Table 5. Molecular docking interactions of the synthesized compounds 5a–5f and 7a–7f
Interacting residues
Interacting residues
Distance,
Å
Distance,
Å
Comp. no.
Comp. no.
receptor
receptor
(2XCT)
ligand
ligand
(2XCT)
5a
5b
5b
5b
5c
5c
5d
5e
5e
5f
NH
NH
NH
NH
NH
NH
NH
O
ASP437- OD2
GLU435-OE2
GLU435-OE2
GLU435-OE1
ASP437- OD1
ASP437- OD2
ASP437-OD2
SER438-NH
GLU435-OE1
SER438-NH
3.01
2.23
2.57
3.04
2.93
2.99
2.98
2.92
3.06
2.76
7a
7a
7b
7c
7c
7d
7e
7e
7f
NH
NH
NH
NH
NH
NH
O
GLU435- OE2
GLU435- O
HIS1081-O
3.07
3.28
4.09
2.91
3.08
2.88
3.09
3.10
3.03
GLU435-OE2
GLY459-O
GLU435-O
GLY459-NH
GLU435-OE2
GLY459-NH
NH
O
NH
O
1
cm–1: 3032 (Ar–CH), 1602 (C=N), 1514 (C=C), 796
1352–1012 (C–F), 775 (C–S). H NMR spectrum, δ,
ppm: 2.78 s (3H, SCH3), 7.58 d.d (J = 7.7, 3.0 Hz, 1H,
ArH), 7.90– 8.07 m (4H, ArH), 8.43–8.52 m (2H,
ArH), 8.83 d (J = 4.2 Hz, 1H, ArH). LCMS, m/z: 271
[М + Н]+. Found, %: C 66.57; H 4.23; N 10.18.
C15H11FN2S. Calculated, %: C 66.65; H 4.10; N 10.36.
1
(C–S). H NMR spectrum, δ, ppm: 2.97 s (3H, SCH3),
6.91–7.00 m (3H, ArH), 7.23–7.34 m (3H, ArH), 7.60–
7.70 m (3H, ArH). LCMS, m/z: 253 [М + Н]+. Found:
C 71.09; H 4.98; N 11.12. C15H12N2S. Calculated, %:
C 71.40; H 4.79; N 11.10.
2-(Methylthio)-3-[(2-(trifluoromethyl)phenyl]-
1,8-naphthyridine (7b). Colorless solid, mp 182–184°C.
FT–IR spectrum, ν, cm–1: 3032 (Ar–CH), 1664 (C=N),
2-(Methylthio)-3-(4-nitrophenyl)-1,8-naphthyri-
dine (7e). Light yellow solid, mp 181–183°C. FT–IR
spectrum, ν, cm–1: 3085 (Ar–CH), 1637 (C=N), 1552
(C=C), 1398 (N–O), 742 (C–S). 1H NMR spectrum, δ,
ppm: 2.80 s (3H, SCH3), 7.54–7.64 m (1H, ArH), 7.90–
8.09 m (4H, ArH), 8.41–8.55 m (2H, ArH), 8.83 d (J =
4.7 Hz, 1H, ArH). LCMS, m/z: 298 [М + Н]+. Found,
%: C 60.68; H 3.41; N 14.00. C15H11N3O2S. Calculated,
%: C 60.59; H 3.73; N 14.13.
1
1510 (C=C), 1296-1028 (C–F), 775 (C–S). H NMR
spectrum, δ, ppm: 2.96 s (3H, SCH3), 6.87 s (1H,
ArH), 7.05 d (J = 2.2 Hz, 1H, ArH), 7.23 s (1H, ArH),
7.28–7.37 m (3H, ArH), 7.66 d.d (J = 9.0, 4.2 Hz, 2H,
ArH). LCMS, m/z: 321 [М + Н]+. Found, %: C 60.12;
H 3.19; N 8.55. C16H11F3N2S. Calculated, %: C 59.99;
H 3.46; N 8.75.
2-(Methylthio)-3-(2-phenoxyphenyl)-1,8-naphthyri-
dine (7f). Light brown solid, mp 199–201°C. FT–IR
spectrum, ν, cm–1: 3032 (Ar–CH), 1660 (C=N), 1573
3-(4-Methoxyphenyl)-2-(methylthio)-1,8-naphthyri-
dine (7c). Light yellow solid, mp 195–197°C. FT–IR
spectrum, ν, cm–1: 3026 (Ar–CH), 1604 (C=N), 1548
1
(C=C), 1166–1114 (C–O–C), 769 (C–S). H NMR
1
(C=C), 1120 (C–O), 769 (C–S). H NMR spectrum, δ,
spectrum, δ, ppm: 2.76 s (3H, SCH3), 6.78 s (3H,
ArH), 7.45 d.d (J = 7.7, 3.5 Hz, 2H, ArH), 7.75–7.85
m (3H, ArH), 8.14 s (2H, ArH), 8.36 d (J = 6.0 Hz,
2H, ArH), 8.97 d (J = 2.3 Hz, 1H, ArH). LCMS, m/z:
345 [М + Н]+. Found, %: C 73.01; H 4.76; N 8.01%.
C21H16N2OS. Calculated, %: C 73.23; H 4.68; N 8.13.
ppm: 2.86 s (3H, SCH3), 3.81 s (3H, OCH3), 7.64 d
(2H, J = 8.2 Hz, ArH), 8.05 d (1H, J = 8.2 Hz, ArH),
8.26 t (J = 7.5 Hz, 2H, ArH), 8.86 d (J = 5.0 Hz, 3H,
ArH). LCMS, m/z: 283 [М + Н]+. Found, %: C 68.01;
H 5.09; N 9.84. C16H14N2OS. Calculated, %: C 68.06;
H 5.00; N 9.92.
Antibacterial and antifungal activities. Antimicrobial
screening of the newly synthesized compounds 5a–5f
and 7a–7f was carried out using the agar diffusion
method [9]. Antibacterial activity of the compounds
3-(4-Fluorophenyl)-2-(methylthio)-1,8-naphthyri-
dine (7d). White solid, mp 194–196°C. FT–IR spectrum,
ν, cm–1: 3140 (Ar–CH), 1666 (C=N), 1583 (C=C),
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A SIMPLE “GREEN” SYNTHESIS OF NOVEL BIS(3-ARYL-1,8-NAPHTHYRIDIN-2-YL)SULFANES
1237
was assayed against the growth of Escherichia coli
(gram –ve) and Staphylococcus aureus (gram +ve)
species along with the standard antibiotic Pencillin at
concentrations of 100 and 50 ppm (Table 4). Majority
of the compounds exhibited moderate to high activity
against both bacteria. The same compounds 5a–5f, 7a–
7f were screened for their antifungal activity against
Aspergillus niger and Helminthosporium oryzae species
at concentrations 100 and 50 ppm. The antibiotic
Griseofulvin was used as a standard. Majority of
compounds 5a–5f, 7a–7f demonstrated moderate to
high antifungal activity (Table 4).
are the advantages of this method. Antimicrobial activity
of the synthesized compounds was tested against
pathogenic bacteria and fungal strains.
ACKNOWLEDGMENTS
One of the authors (Dharavath Ravi) is thankful to
University Grants Committee, New-Delhi, India for
awarding research fellowship (UGC-SRF) and CFRD-
1
OU, IICT-Hyderabad for IR, H NMR and mass
spectral data.
REFERENCES
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7a–7f were sketched using the tools Chemsketch, and
docked into the target binding sites. The scoring
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According to the accumulated data, compounds 5c,
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The active site pocket residues of DNA Gyrase were
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We have developed an efficient procedure for the
synthesis of new symmetrical bis(3-aryl-1,8-naphthyri-
din-2-yl)sulfanes and unsymmetrical 3-aryl-1,8-
naphthyridine-2-thiol by the reaction of thiourea with
2-chloro-3-aryl-1,8-naphthyridines under microwave
radiation. High yields of the products, easy work-up,
short reaction times, and non-toxicity of the reagents
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 6 2018