An Exceedingly Mild, Green Synthesis of Substituted N-3-diaryl-1,8-naphthyridin-2-amine Derivatives and Their Antimicrobial Activity

Article abstract of DOI:10.1002/jhet.3125

An exceedingly and highly efficient procedure has been described for the synthesis of substituted N-3-diaryl-1,8-naphthyridin-2-amines by the reaction of 2-chloro-3-aryl-1,8-naphthyridines with various anilines in the presence of N-methyl-2-pyrrolidone and K₂CO₃ under thermal green solvent-free conditions. The significant features of this green reaction include very good yields in purity, simple experimental, short reaction time, easy workability, and avoidance of toxic solvents. All synthesized compounds have been evaluated for their antibacterial activity.

Full text of DOI:10.1002/jhet.3125

Month 2018
An Exceedingly Mild, Green Synthesis of Substituted N-3-diaryl-1,8-
naphthyridin-2-amine Derivatives and Their Antimicrobial Activity
*
Dharavath Ravi, Sirgamalla Rambabu, Kommakula Ashok, Palithapu Madhu, and Boda Sakram
Department of Chemistry, Osmania University, Hyderabad 500007, Telangana, India
*
E-mail: bschemou@gmail.com
Received October 16, 2017
DOI 10.1002/jhet.3125
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
An exceedingly and highly efficient procedure has been described for the synthesis of substituted N-3-
diaryl-1,8-naphthyridin-2-amines by the reaction of 2-chloro-3-aryl-1,8-naphthyridines with various anilines
in the presence of N-methyl-2-pyrrolidone and K2CO3 under thermal green solvent-free conditions. The sig-
nificant features of this green reaction include very good yields in purity, simple experimental, short reaction
time, easy workability, and avoidance of toxic solvents. All synthesized compounds have been evaluated for
their antibacterial activity.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
conditions [22,23]. The field of solvent-free organic
fusion admiration to experimental processes and covers
all branches of organic chemistry. Resulting yields are
remarkably high starting from stoichiometric amount of
reactants, especially in the case of solid–solid reactions.
Moreover, the advantage of green synthesis, interesting
properties like simple procedures, the process is
environmentally natural, efficient workup procedures,
hazards, low costs, simplicity, reaction times can be
dramatically shortened and minimization of energy
consumption. It is now known that many chemical
conversions example formation of C–N that was reported
to require solid supports with catalytic activity [24,25]. It
has been exposed that with neat reaction, solvents can be
boiled above their boiling points, and it may be explained
that it is this form of superheated, and the reactions take
place rapidly, which leads to observed rate improvements
for many reactions; these would be especially significant
during industrial manufacture [26]. In green chemistry, as
previously mentioned [27], the solvents are to be used as
the source of solid-state grinding, and they must couple it
successfully with eco-friendly synthetic processes. In this
paper, we would like to report a fast, practical, and facile
In recent years, research on derivatives of 1,8-
naphthyridines represents an significant class of
organic molecules that attract the interest of medicinal
chemists because of their extremely wide spectrum of bio-
organic/chemical/medicinal/pharmaceutical and biological
importance [1–4] as well as their use as important binding
units in the molecular plan of synthetic receptors [5]. 1,8-
naphthyridine derivatives attract the interest of much
biological importance, such as anti-tumor [6–8], anti-
mycobacterial [9], anti-allergic [10,11], antibacterial [12–14],
anti-inflammatory [15], anti-hypertensive [16], anti-HIV
[17] and local anesthetic [18]. Gemifloxacin has both
antimicrobial and antibacterial activities [2]. Some of new
1,8-naphthyridine derivatives including benzo [1,8]
naphthyridine have recently been patented as growth
regulators, nemathocides, herbicides, insecticides, and
fungicides of new generation [19–21]. Some of the
biologically potent 1,8-naphthyridines derivatives are
shown in Figure 1.
Nowadays, increasingly attractive to researchers due to
developing and interest has been focused on solvent-free
© 2018 Wiley Periodicals, Inc.

D. Ravi, S. Rambabu, K. Ashok, P. Madhu, and B. Sakram
Vol 000
Figure 1. Biologically potent of 1,8-naphthyridines derivatives.
protocol for the creation of substituted N-3-diaryl-1,8-
naphthyridin-2-amine derivatives under thermal green
solvent-free conditions (Scheme 1).
NaNO2. Treatment of compounds 4 with POCl3 under
MWI yielded 2-chloro-1,8-naphthyridines 5 was prepared
following the literature procedure [31]. The reactions
proceed efficiently in excellent yields at ambient pressure
within few minutes. A remarkable influence of the
nucleophilic substitution of chlorine at position 2 in
3-aryl-2-chloro-1,8-naphthyridine substituents by different
substituents in all three cases anilines (X = F, Cl, Br)
outcome of this reaction to produce N-3-diaryl-1,8-
naphthyridin-2-amines. To detect the effect of substituents
on 2-chloro-3-aryl-1,8-naphthyridines on the reaction,
o-methoxyphenyl-1,8-naphthyridine and p-methoxyphenyl-
1,8-naphthyridine (bearing electron-donating methoxyl
groups) and p-chlorophenyl-1,8-naphthyridine (containing
electron-withdrawing chloride) were chosen as the
substrates. The results are listed in Table 1.
RESULTS AND DISCUSSION
In continuation of our exploration for new catalysts
[28–30] convenient herein, we wish to report an
exceedingly, mildly, and highly efficient procedure for the
synthesis of several substituted aryl at the N and C-3
position of the 1,8-naphthyridine ring; compounds
are profiled in Scheme 1. Condensation of 2-
aminonicotinaldehyde 1 with 2-phenyl acetonitrile 2 in
the presence of 10% potassium hydroxide (KOH) without
any solvent under microwave irradiation (MWI) afforded
2-amino-1,8-naphthyridines 3, which is converted into
1,8-naphthyridine-2(1H)-ones 4 by the reaction with
In this research, 2-chloro-3-aryl-1,8-naphthyridines
(5a–d) used as a suitable intermediate for the synthesis of
Scheme 1. Synthetic route for the synthesis of N-3-diaryl-1,8-naphthyridin-2-amine derivatives.
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Synthesis and Biological Activity of New N-3-diaryl-1,8-naphthyridin-2-amines
Table 1
Synthesis of N-3-diaryl-1,8-naphthyridin-2-amine derivatives (7a–l).
Entry
1
Amine
Producta
Time (min)
25
Yield (%)b
86
Mp (°C)
196–198
2
20
88
220–222
3
4
25
30
84
90
233–235
250–252
5
30
92
268–270
6
7
25
20
88
85
232–234
208–210
8
9
25
25
91
84
225–227
201–202
(Continues)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

D. Ravi, S. Rambabu, K. Ashok, P. Madhu, and B. Sakram
Vol 000
Table 1
(Continued)
Entry
10
Amine
Producta
Time (min)
20
Yield (%)b
92
Mp (°C)
260–262
11
12
25
20
88
91
244–246
230–232
aReaction conditions: 2-chloro-3-aryl-1,8-naphthyridine (5,1 mmol), p-fluoro or p-chloro, or p-bromoanilines (6, 1 mmol), N-methyl-2-pyrrolidone
(10 mmol), K2CO3 (3.5 mmol), 75°C, neat conditions.
bIsolated yields after purification.
target compounds. N,3-diaryl-1,8-naphthyridin-2-amines
(7a–l) were synthesized an exceeding method by 2-
chloro-3-aryl-1,8-naphthyridines (5a–d) with various p-
amino phenyl halides at the ratio of 1:1 in the presence of
dry N-methyl2-pyrrolidone (NMP), and K2CO3 under
green/ solvent-free conditions, the progress of the
reaction was monitored by TLC. The experimental
procedure is very simple and completed in 20–30 min
(Table 1). The reaction is very rapid, good yields
(84–92%), and the products were obtained with a high
degree of purity by this procedure. This displayed that
NMP acts as an active catalyst in this reaction.
Furthermore, the solvent-free reaction has many
advantages: low costs, reduced pollution, and simplicity in
process and handing.
determined as 406 (M + H) by LC–MS–MS. Its
IR spectrum shows an absorption at 3167 cmÀ1 for
NH group, 1138 cmÀ1 for OCH3 group, and 705 cmÀ1
for C–Br group. Its 1H nuclear magnetic resonance
(NMR) spectrum exhibited a singlet at δ 12.30 ppm for
NH group and aromatic hydrogen group range between δ
7.02 and 8.51 ppm. The methoxyl hydrogen (singlet)
resonated at 3.81 ppm was also detected clearly.
EXPERIMENTAL
Materials and methods. All the materials and reactants
were used as purchased from Aldrich Chemical Company
and were used without further purification. The purity of
the compounds was checked by TLC silica gel plates
(60 F-254, Merck KGaA64271 Darmstadt, Germany)
with hexane: ethyl acetate as eluent, and spots were
visualized in iodine vapor. All the melting points
were determined in open capillary tubes using Cintex
apparatus (Cintex Industrial Corporation, Mumbai,
India) and were uncorrected. IR spectra were
distinguished on a Perkin Elmer FTIR spectrophotometer
In
a
typical experimental procedure, equimolar
quantities of 2-chloro-3-phenyl-1,8-naphthyridine 5a, p-
bromoaniline in NMP, and K2CO3 were added to the
mixture, heated to 75°C for 25 min under neat condition.
The precipitated product was filtered. After usual
workup N-(4-bromophenyl)-3-phenyl-1,8-naphthyridin-2-
amine 7a was obtained in 86% yield. The reaction is of
general applicability different compounds (5b–d) and
(6b–c) to substituted N-3-diaryl-1,8-naphthyridin-2-amine
compounds (7b–l) were synthesized, and recrystallized in
methanol for more purification.
1
(Waltham, MA) using KBr pellets. The H NMR spectra
were recorded on Varian Gemini 400 MHz instrument
(Palo Alto, CA) using TMS as an internal standard in
DMSO-d6. Chemical shifts are expressed in parts
Structures 7a–l was established by elemental
analysis and spectral data. For example, the molecular
weight for N-(4-bromophenyl)-3-(4-methoxyphenyl)-1,8-
per million. Microanalyses were performed on
a
Carlo-Erba model EA1108 analytical unit (Carlo Erba
Manasquan, NJ).
naphthyridin-2-amine
(7d,
C21H16BrN3O)
was
Journal of Heterocyclic Chemistry
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Month 2018
Synthesis and Biological Activity of New N-3-diaryl-1,8-naphthyridin-2-amines
General procedure for the synthesis of 3-phenyl-1,8-
naphthyridin-2-amines (3a–d).
ArH), 12.40 (1H, s, NH); MS [EI, m/z(%)]: 315 (M + H)+;
Anal. Calcd for C20H14FN3: C, 76.18; H, 4.48; N, 13.33;
found: C, 76.01; H, 4.42; N, 13.22%.
A
mixture of 2-
aminonicotinaldehyde 1 (1 mmol, 122.12 mg) and aryl
acetonitrile 2 (1 mmol) in 10% KOH (five drops) was
exposed to MWI at 400 W intermittently at 30 s intervals
for 2.5–3.0 min. On completion of reaction, as monitored
by TLC, the reaction mixture was cooled and treated with
chilled water. The solid that precipitated was filtered,
washed with water, and recrystallized from ethanol to
N-(4-chlorophenyl)-3-phenyl-1,8-naphthyridin-2-amine
(7c).
Half-white solid; yield 2.78 g; IR (KBr, νmax,
cmÀ1): 3235, 3130, 1510, 1311, 1214; 1Н NMR
(400 MHz, DMSO-d6, ppm): δ 7.25–7.33 (2H, m, ArH),
7.37–7.48 (4H, m, ArH), 7.70–7.80 (3H, m, ArH), 8.09–
8.19 (3H, m, ArH), 8.48–8.54 (1H, m, ArH), 12.35 (1H,
s, NH); MS [EI, m/z(%)]: 331 (M + H)+; Anal. Calcd for
C20H14ClN3: C, 72.40; H, 4.25; N, 12.66; found: C,
72.51; H, 4.40; N, 12.42%.
give compound (3a–d) with good yields.
General procedure for the synthesis of 3-phenyl-1,8-
naphthyridin-2(1H)-one (4a–d). To a cold solution of 3 (1
mmol) in 2 M HCl (25 ml) was added NaNO2 solution (1
mmol in 25 ml water) and the reaction mixture was stirred
at room temperature for 0.5 hr. The progress of the reaction
was monitored by TLC. After completion of the reaction,
the mixture was poured into ice-cold water. The solid thus
obtained was filtered, washed with water, and recrystallized
N-(4-bromophenyl)-3-(4-methoxyphenyl)-1,8-naphthyridin-2-
amine (7d). Yellow solid; yield 3.65 g; IR (KBr, νmax
,
1
cmÀ1): 3167, 1510, 1421, 1138, 705; Н NMR (400 MHz,
DMSO-d6, ppm): δ 3.81 (3H, s, ArOCH3), 7.02 (2H, d,
J = 9.0 Hz, ArH), 7.22–7.30 (3H, m, ArH), 7.70–7.79 (3H,
m, ArH), 7.90 (1H, d, J = 2.2 Hz, ArH), 8.08 (1H, s, ArH),
8.51 (2H, s, ArH), 12.30 (1H, s, NH); MS [EI, m/z(%)]:
406 (M + H)+; Anal. Calcd for C21H16BrN3O: C, 62.08; H,
3.97; N, 10.34; found: C, 62.20; H, 3.80; N, 10.30%.
from ethanol to afford (4a–d) with good yields.
General procedure for the synthesis of 2-chloro-3-phenyl-
1,8-naphthyridine (5a–d).
A solution of 4 (1 mmol) in
POCl3 (15 mL) was exposed to MWI at 200 W
intermittently at 30 s intervals for 2.0–2.5 min. After the
reaction mixture was cooled to room temperature, the
resulting reaction mixture was dissolved in cold H2O
(2 × 75 mL) and saturated NaHCO3. The organic phase
was dried and evaporated to dryness. The crude product
was filtered, washed with water, and recrystallized from
N-(4-fluorophenyl)-3-(4-methoxyphenyl)-1,8-naphthyridin-
2-amine (7e). Gray solid; yield 3.17 g; IR (KBr, νmax
,
cmÀ1): 3207, 1519, 1415, 1181, 891; 1Н NMR
(400 MHz, DMSO-d6, ppm): δ 3.81 (3H, s, ArOCH3),
6.96–7.05 (3H, m, ArH), 7.15 (2H, s, ArH), 7.38–7.47
(3H, m, ArH), 8.10 (2H, s, ArH), 8.43–8.52 (2H, m,
ArH), 12.33 (1H, s, NH); MS [EI, m/z(%)]: 345
(M + H)+; Anal. Calcd for C21H16FN3O: C, 73.03; H,
4.67; N, 12.17; found: C, 73.10; H, 4.71; N, 12.33%.
N-(4-chlorophenyl)-3-(4-methoxyphenyl)-1,8-naphthyridin-
n-pentane to furnish 5a–d.
General procedure for the synthesis of N-3-diaryl-1,8-
naphthyridin-2-amines (7a–l).
A mixture of 2-chloro-3-
aryl-1,8-naphthyridine (1 mmol, 5a–d), p-amino phenyl
halides (1 mmol, 6a–c), 10 mmol of dry NMP and
K2CO3 (3.5 mmol) under solvent-free conditions at 75°C
for 20–30 min. During this time, the progress of the
reaction was followed by the TLC test (Table 1). When the
reaction was completed, cooled to room temperature and
poured into a mixture of ethyl acetate. The solid separated
out was filtered, washed with water, and recrystallized
from methanol to furnish 7a–l with good yields.
2-amine (7f). Colorless solid; yield 3.18 g; IR (KBr, νmax
,
cmÀ1): 3309, 1520, 1154, 1021, 751; 1Н NMR (400 MHz,
DMSO-d6, ppm): δ 3.81 (3H, s, ArOCH3), 7.05 (2H, d,
J = 8.5 Hz, ArH), 7.20–7.27 (2H, m, ArH), 7.50 (1H, s,
ArH), 7.72–7.80 (3H, m, ArH), 8.19–8.25 (1H, m, ArH),
8.64 (1H, s, ArH), 8.71 (2H, s, ArH), 12.38 (1H, s, NH);
MS [EI, m/z(%)]: 362 (M + H)+; Anal. Calcd for
C21H16ClN3O: C, 69.71; H, 4.46; N, 11.61; found: C,
69.87; H, 4.56; N, 11.55%.
Spectral data of representative compounds. N-(4-
bromophenyl)-3-phenyl-1,8-naphthyridin-2-amine (7a). Pale-
N-(4-bromophenyl)-3-(2-methoxyphenyl)-1,8-naphthyridin-2-
amine (7g). Pale-yellow solid; yield 3.46 g; IR (KBr, νmax
,
yellow solid; yield 3.24 g; IR (KBr, νmax, cmÀ1): 3313,
3170, 3026, 1546, 1325, 694; 1Н NMR (400 MHz,
DMSO-d6, ppm): δ 7.28 (1H, dd, J = 7.7, 4.7 Hz, ArH),
7.36–7.53 (5H, m, ArH), 7.69–7.80 (3H, m, ArH), 8.13
(1H, s, ArH), 8.17 (2H, dd, J = 7.7, 1.6 Hz, ArH), 8.52
(1H, dd, J = 4.7, 1.7 Hz, ArH), 12.35 (1H, s, NH); MS [EI,
m/z(%)]: 375 (M+); Anal. Calcd for C20H14BrN3: C, 63.84;
1
cmÀ1): 3360, 3028, 1508, 1136, 692; Н NMR (400 MHz,
DMSO-d6, ppm): δ 3.80 (3H, s, ArOCH3), 7.01 (2H, d,
J = 8.0 Hz, ArH), 7.22–7.27 (2H, m, ArH), 7.46–7.58 (1H,
m, ArH), 7.73 (2H, d, J = 9.0 Hz, ArH), 7.90 (1H, s, ArH),
8.08 (1H, s, ArH), 8.12–8.17 (1H, m, ArH), 8.51 (2H, s,
ArH), 12.30 (1H, s, NH); MS [EI, m/z(%)]: 406 (M + H)+;
Anal. Calcd for C21H16BrN3O: C, 62.08; H, 3.97; N, 10.34;
found: C, 62.21; H, 3.83; N, 10.23%.
N-(4-fluorophenyl)-3-(2-methoxyphenyl)-1,8-naphthyridin-
H, 3.75; N, 11.17; found: C, 63.90; H, 3.70; N, 11.00%.
N-(4-fluorophenyl)-3-phenyl-1,8-naphthyridin-2-amine
(7b). White solid; yield 2.77 g; IR (KBr, νmax, cmÀ1):
2-amine (7h). Gray solid; yield 3.14 g; IR (KBr, νmax
,
3273, 3167, 3030, 1508, 1278, 1155; 1Н NMR (400 MHz,
DMSO-d6, ppm): δ 7.24–7.35 (5H, m, ArH), 7.76–7.85
(3H, m, ArH), 8.10–8.20 (3H, m, ArH), 8.50–8.59 (2H, m,
cmÀ1): 3320, 1581, 1056, 996; 1Н NMR (400 MHz,
DMSO-d6, ppm): δ 3.80 (3H, s, ArOCH3), 7.28 (2H, dd,
J = 7.7, 4.8 Hz, ArH), 7.44–7.56 (3H, m, ArH), 7.78
Journal of Heterocyclic Chemistry
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D. Ravi, S. Rambabu, K. Ashok, P. Madhu, and B. Sakram
Vol 000
(3H, t, J = 2.3 Hz, ArH), 8.09–8.26 (3H, m, ArH), 8.53
(1H, dd, J = 4.7, 1.6 Hz, ArH), 12.41 (1H, s, NH); MS
[EI, m/z(%)]: 345 (M
C21H16FN3O: C, 73.03; H, 4.67; N, 12.17; found: C,
73.20; H, 4.82; N, 12.33%.
N-3-bis (4-chlorophenyl)-1,8-naphthyridin-2-amine (7l).
Colorless solid; yield 3.33 g; IR (KBr, νmax, cmÀ1): 3356,
3030, 1489, 1222, 767, 731; 1Н NMR (400 MHz,
DMSO-d6, ppm): δ 7.24–7.35 (4H, m, ArH), 7.73–7.87
(3H, m, ArH), 8.08–8.23 (3H, m, ArH), 8.48–8.60 (2H,
m, ArH), 12.39 (1H, s, NH); MS [EI, m/z(%)]: 366
(M + H)+; Anal. Calcd for C20H13Cl2N3: C, 65.59; H,
3.58; N, 11.47; found: C, 65.49; H, 3.52; N, 11.51%.
+
H)+; Anal. Calcd for
N-(4-chlorophenyl)-3-(2-methoxyphenyl)-1,8-naphthyridin-
2-amine (7i). Cream solid; yield 3.02 g (84%); IR (KBr,
ν
max, cmÀ1): 3358, 3028, 1508, 1423, 1060, 775; 1Н
NMR (400 MHz, DMSO-d6, ppm): δ 3.80 (3H, s,
ArOCH3), 7.04 (3H, d, J = 11.5 Hz, ArH), 7.51 (1H, d,
J = 20.5 Hz, ArH), 7.70–7.81 (3H, m, ArH), 7.90 (1H, s,
ArH), 8.08 (1H, s, ArH), 8.17 (3H, d, J = 11.5 Hz, ArH),
12.30 (1H, s, NH); MS [EI, m/z(%)]: 362 (M + H)+;
Anal. Calcd for C21H16ClN3O: C, 69.71; H, 4.46; N,
Antibacterial activity.
The title compounds as
potentially useful compounds with possible biological
activities. The compounds 7a–l were protected for their
antibacterial activity against Bacillus subtilis (Gram-
positive) and Escherichia coli (Gram-negative) by filter
paper disc technique [32] at 400 and 600 μg/disc
concentrations. Streptomycin antibiotic was used as
standard for the antibacterial activity, under similar
conditions. The results of the antibacterial screening are
given in Table 2.
The agar diffusion method was used for antibacterial
activity was evaluated by measuring the diameter of the
zones of inhibition against the tested bacteria. The test
organisms were subcultured on lysogeny broth. Take 1 μ
of Luria Bertani (LB broth powder) and dissolve in 10 ml
of distilled water in a test tube and autoclaved at 15-lb
pressures for 15 min and cool. Then add 400 and 600 μg/
disc of bacterial culture to the broth in laminar air flow
and stored at 4°C in the refrigerator. For bacterial assay,
nutrient agar (40 g/mL) was used for developing surface
colony growth. Stock solution of each compound was
prepared at a concentration of 1 μ/mL. The diameter of
the inhibition zone in millimeter was measured, and the
activity index was also calculated. About 100 μL of 400
and 600 μg/disc concentrations of compounds were
11.61; found: C, 69.80; H, 4.55; N, 11.35%.
N-(4-bromophenyl)-3-(4-chlorophenyl)-1,8-naphthyridin-2-
amine (7j). Pale-yellow solid; yield 3.77 g; IR (KBr, νmax
,
cmÀ1): 3358, 3030, 1487, 1274, 767, 732; 1Н NMR
(400 MHz, DMSO-d6, ppm): δ 7.28 (2H, d, J = 1.9 Hz,
ArH), 7.52 (3H, d, J = 8.6 Hz, ArH), 7.80 (3H, d,
J = 4.6 Hz, ArH), 8.11–8.24 (3H, m, ArH), 8.54 (1H, d,
J = 9.7 Hz, ArH), 12.41 (1H, s, NH); MS [EI, m/z(%)]:
410 (M + H)+; Anal. Calcd for C20H13BrClN3: C, 58.49;
H, 3.19; N, 10.23; found: C, 58.53; H, 3.32; N, 10.12%.
3-(4-chlorophenyl)-N-(4-fluorophenyl)-1,8-naphthyridin-2-
amine (7k).
White solid; yield 3.08 g; IR (KBr, νmax,
cmÀ1): 3356, 3030, 1510, 1278, 1157, 738; 1Н NMR
(400 MHz, DMSO-d6, ppm): δ 7.28 (2H, dd, J = 7.7,
4.8 Hz, ArH), 7.50–7.55 (3H, m, ArH), 7.77–7.82 (3H,
m, ArH), 8.17 (1H, d, J = 1.6 Hz, ArH), 8.19 (2H, s,
ArH), 8.53 (1H, dd, J = 4.7, 1.7 Hz, ArH), 12.41 (1H, s,
NH); MS [EI, m/z(%)]: 350 (M + H)+; Anal. Calcd for
C20H13ClFN3: C, 68.67; H, 3.75; N, 12.01; found: C,
68.73; H, 3.82; N, 12.12%.
Table 2
Antibacterial activity screening data of the synthesized compounds 7a–l.
Inhibition zone (in mm) against
Escherichia coli at
Bacillus subtilis at
Compound
400 μg/disc
600 μg/disc
400 μg/disc
600 μg/disc
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
6.5
6.0
6.5
10.0
8.0
11.0
7.5
6.5
7.5
8.0
7.5
7.5
7.0
7.5
11.0
9.5
12.0
8.5
7.5
6.0
9.0
8.0
4.0
4.0
5.0
7.0
6.0
6.5
5.0
5.5
4.0
5.5
5.0
8.0
10.0
5.0
5.0
6.0
8.0
7.0
7.5
6.0
6.0
5.5
6.5
6.0
8.5
12.0
10.5
13.0
11.5
15.0
Streptomycin
The results for 7f and 7l are highest antibacterial activity compared with 7a–e and 7g–k.
Bold values shows more activity compared to other antibacterial compounds.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis and Biological Activity of New N-3-diaryl-1,8-naphthyridin-2-amines
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added by sterile pipette into the wells and allowed to
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37°C for 15–22 h for bacterial pathogens. For each
replicates, the readings were taken in three different fixed
directions, and the values were recorded.
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The activity of the synthesized compounds depends upon
the nature and position of the substituent at the phenyl
moiety. The presence of certain flouro-substituted, chloro-
substituted, and bromo-substituted aryl group diminishes
the activity of the compounds. On the other hand, certain
substituents especially methoxyl and chloro groups when
attached to phenyl ring augment the antibacterial activity
remarkably. In the case of E. coli, the compound 7f is
showing maximum antimicrobial activity against gram-
negative bacteria, and 7d and 7l are nearest to standard
drug, whereas the compound 7l is showing equipotent
antimicrobial activity with streptomycin drug in the case
of B. subtilis. We report herein the first structure–activity
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varying the N-(4-bromophenyl)-3-(4-methoxyphenyl)-1,8-
naphthyridin-2-amine (7d) and N-(4-bromophenyl)-3-(2-
methoxyphenyl)-1,8-naphthyridin-2-amine (7g). When
methoxyl was a phenyl ring, para-substitution was found
to be superior to ortho-substitution. While the electron-
donating of substituents position 4-methoxyphenyl
compound (7d) was well tolerated, but 2-methoxyphenyl
(7g) was not. All the compounds are showing good to
moderate antibacterial activity.
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CONCLUSIONS
In conclusion, a mild and highly efficient method has
been developed for the synthesis of novel N-substituted
1,8-naphthyridin-2-amines. Moreover, in solvent-free
conditions make syntheses good to excellent yields,
obviously reduce pollution, easy work-up, short reaction
time, simpler and excellent purities of the products. The
antibacterial activity of synthesized compounds 7d, 7f,
and 7l exhibits uppermost activity to that of streptomycin
towards E. coli.
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Acknowledgments. I am thankful to my supervisor Dr. B.
Sakram and the Head, Department of Chemistry, Osmania
University, for providing laboratory facilities and Directors,
CFRD-OU-Hyderabad, for providing spectral data. D. Ravi
thanks the University Grant Commission (UGC), New Delhi,
for providing research fellowships.
SUPPORTING INFORMATION
REFERENCES AND NOTES
Additional Supporting Information may be found online
in the supporting information tab for this article.
[1] Roma, G.; DiBraccio, M.; Grossi, G.; Piras, D.; Ballabeni, V.;
Tognolini, M.; Bertoni, S.; Barocelli, E. Eur J Med Chem 2010, 45, 352.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet