Green Synthesis of Fused Imidazo[1,2-a][1,8]naphthyridine Derivatives Catalyzed by DABCO under Solvent-Free Solid-State Conditions and Their Biological Evaluation

Article abstract of DOI:10.1002/jhet.3092

An efficient and eco-friendly methodology has been developed for the construction of fused imidazo[1,2-a][1,8]naphthyridine derivatives in the presence of 1,4-diazabicyclo[2.2.2]octane, and involving various substituted heterocyclic amines with phenacyl b

Full text of DOI:10.1002/jhet.3092

Month 2018
Green Synthesis of Fused Imidazo[1,2-a][1,8]naphthyridine Derivatives
Catalyzed by DABCO under Solvent-Free Solid-State Conditions and
Their Biological Evaluation
a
b
a
*
Sonyanaik Banoth, Shyam Perugu, and Sakram Boda
aDepartment of Chemistry, Osmania University, Hyderabad 500007, Telangana, India
bBiomedical Informatics Center, National Institute of Nutrition, Tarnaka, Hyderabad 50007, India
*
E-mail: bschemou@gmail.com
Received July 15, 2017
DOI 10.1002/jhet.3092
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
An efficient and eco-friendly methodology has been developed for the construction of fused imidazo[1,2-a]
[1,8]naphthyridine derivatives in the presence of 1,4-diazabicyclo[2.2.2]octane, and involving various
substituted heterocyclic amines with phenacyl bromide under solvent-free solid-state condition obtained the
corresponding compounds (5a–g, 7a–f) in short reaction time with high yield which is the important features
of this protocol. All newly synthesized products were evaluated for their antibacterial and fungal activities. All
these compounds displayed good antibacterial and antifungal activity. In predominantly, compounds 7e, 7d,
and 5d demonstrate the highest antibacterial and antifungal activities. Furthermore, in silico molecular
docking studies results were well complemented to the antimicrobial activity.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
In recent years, development of organic reactions in the
solvent-free solid-state grinding method has been attracting
to the synthetic organic researchers and medicinal
chemists. Meanwhile, solid-state reactions without using
harmful solvent are of great interest especially in relation to
environmental concerns today and have unique advantages
on high purity of the products, cost-effectiveness, reduction
in pollution, environmentally benign procedure, and
simplicity in handling make this protocol “green” and eco-
friendly [10–13]. Nowadays, much attention has been
directed towards the development of green chemical
processes as the environmentally sustainable methods,
chemicals, and reagents [14,15]. In continuation of our
previous studies on the development of eco-friendly
methodologies [16–18], we have developed a simple,
convenient, and environmentally benign synthesis of fused
imidazo[1,2-a][1,8]naphthyridine derivatives. To the best of
Nitrogen atom containing heterocyclic compounds play
key role in the field of medicinal chemistry [1]. Among
these
heterocyclic
compounds
1,8-naphthyridine
derivatives possess broad range of useful biological
properties establish in therapeutic and medicinal research.
1,8-Naphthyridine scaffolds possess broad spectrum of
beneficial pharmacological activities that include anti-
inflammatory [2], anti-HIV [3], antimicrobial [4], and
antitumor activities [5]. 1,8-Naphthyridine derivatives
have also exhibited potential applications in neurological
disorders such as Alzheimer’s disease [6]. In addition,
they possess activities such as antimalarial [7], anti-
allergic [8], and antituberculosis activities [9]. Some of
the biologically potent 1,8-naphthyridine derivatives are
shown in Figure 1.
© 2018 Wiley Periodicals, Inc.

S. Banoth, S. Perugu, and S. Boda
Vol 000
Figure 1. Some of the biologically active 1,8-naphthyridines.
our knowledge, there is no grinding method that has been
reported in the literature for the construction of fused
imidazo[1,2-a][1,8]naphthyridine scaffolds utilizing, 4-
diazabicyclo[2.2.2]octane (DABCO) as catalyst under
solvent-free solid-state conditions.
a kind of “stirring.” To develop an eco-friendly green
methodology, we have synthesized novel fused
imidazo[1,2-a][1,8]naphthyridine scaffolds using under
the solvent-free grinding method by involving 2-
aminonicotinaldehyde
phenylacetonitrile
obtained corresponding
1
on
in the presence of piperidine
compound 2-amino-1,8-
condensation
with
2
RESULTS AND DISCUSSION
naphthyridines 3 at room temperature according to the
literature procedure [23], and then 2-amino-1,8-
naphthyridines reacted with 2-bromo-1-(4-chlorophenyl)
ethan-1-one 4 in the presence of DABCO (10 mol %)
11.2 mg in water (5 mL) interestingly furnished
corresponding 9-(4-chlorophenyl)-6-phenylimidazo[1,2-a]
[1,8]naphthyridine derivatives (5a–g) with good yields,
and then the same reaction carried out 3-(2-bromoacetyl)-
2H–chromen-2-one 6 instead of 2-bromo-1-(4-chloro-
phenyl)ethan-1-one obtained 3-(6-phenylimidazo[1,2-a]
A
representation for the construction of fused
imidazo[1,2-a][1,8]naphthyridine derivatives (5a–g, 7a–f)
catalyzed by DABCO under solvent-free solid-state
condition is exposed in Scheme 1.
Solid-state reactions transpired competently and more
selectively than the solution phase reactions [19]. The
present work, grinding method is eco-friendly, requires
no special apparatus and non-hazardous solvents. Rate
accelerations can be described because of the conversion
of mechanical energy (kinetic energy applied due to
grinding) into heat energy, which becomes the driving
force for improved activation of molecules. The kinetic
energy provided during grinding can have various
effects on a crystalline solid [20–22] which exclusively is
[1,8]naphthyridin-9-yl)-2H–chromen-2-one
derivatives
(7a–f) with good yields in short reaction time. The
reaction is facile and efficient and is devoid of any side
products. The route is environmentally benign. The
experimental procedure is simple and avoids
sophistication.
Scheme 1. Synthesis of novel fused imidazo[1,2-a][1,8]naphthyridine scaffolds under solvent-free solid-state condition.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Green Synthesis of Fused Imidazo[1,2-a][1,8]naphthyridine Derivatives and Their
Biological Evaluation
Table 1
EXPERIMENTAL
Synthesis of fused imidazo[1,2-a][1,8]naphthyridine derivatives (5a–g,
7a–f) under solvent-free solid-state conditions.
Materials and chemicals. All the solvents and chemicals
were purchased from Aldrich/ Merck and used without
further purification. Melting points were determined in
open capillaries using Buchi melting point apparatus and
are uncorrected. The progress of the reactions and purity
of the compounds were monitored by thin layer
chromatography (TLC) with F254 silica-gel precoated
aluminum sheets using hexane/ethyl acetate (7/3) as
eluent. Infrared (IR) spectra were recorded on Perkin-
Elmer 100S spectrophotometer (PerkinElmer, Inc.
Waltham, MA) using KBr pellet. NMR spectra were
recorded on Bruker 400 MHz spectrometer (Bruker,
Bengaluru, Karnataka, India) using hexadeuterated
dimethyl sulfoxide (DMSO-d6) as solvent and
tetramethylsilane as an internal standard. Mass spectra
(electrospray ionization) were recorded on a Jeol JMSD-
300 spectrometer (Jeol, India). Elemental analyses were
performed on a Carlo Erba EA 1108 automatic elemental
analyzer (Carrer Filadors, Sabadell, Barcelona, Spain).
Time
(min)
Yielda
(%)
Melting points
(°C)
Entry Analog
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
7a
7b
7c
7d
7e
7f
4
5
6
4
6
5
5
6
5
4
5
4
4
87
90
88
86
85
83
91
87
89
85
87
89
84
273
252
295
246
287
304
312
291
317
249
281
325
329
9
10
11
12
13
aIsolated yields after purification.
9-(4-chlorophenyl)-6-phenyl
imidazo[1,2-a][1,8]
naphthyridine (5a). Brown solid; IR (KBr) (λmax, cmÀ1):
1658 (C═C), 1606, (C═N), 833 (C-Cl); 1H NMR
(400 MHz; DMSO-d6), δ, ppm: 8.83 (s, 1H), 8.02 (d, 2H,
J = 7.2 Hz), 7.76 (d, 2H, J = 7.2 Hz), 7.94 (m, 5H), 6.87
(m, 4H); 13C NMR (400 MHz; DMSO-d6), δ, ppm:
148.9, 147.2 (2C), 143.5, 142.1 (2C), 141.8, 140.1,
138.6, 136.3, 135.4, 133.6, 132.2, 130.6 (2C), 129.7
(2C), 128.2, 126.4, 125.8, 118.6; Anal. Calcd for
C22H14ClN3C (355): C, 74.26; H, 3.97; N, 11.81; Found:
C, 74.49; H, 4.12; N, 11.73.
General
procedure
for
the
synthesis
of
3-phenyl-1,8-naphthyridin-2-amines (3a–g).
To take
compound 2-amino-nicotinaldehyde
1
(1 mmol,
122.12 mg), aryl acetonitrile 2 (1 mmol) and added
catalytic amount of piperidine were ground in a mortar
pestle and interestingly obtained the desired product (3a–g)
with good yields. After completion of the reaction
(monitored by the TLC), the reaction mixture was poured
into cold water. The product, which separated, was filtered,
washed with water, and purified by recrystallization from
methanol to obtain the pure products.
9-(4-chlorophenyl)-6-(4-fluorophenyl)
naphthyridine (5b).
imidazo[1,2-a][1,8]
White compound; IR (KBr) (λmax
,
cmÀ1): 1663 (C═C), 1604, (C═N), 829 (C─Cl); 1H
NMR (400 MHz; DMSO-d6), δ, ppm: 8.97 (s, 1H), 8.37
(d, 2H, J = 7.2 Hz), 7.86 (d, 2H, J = 7.2 Hz), 7.36–7.21
(m, 4H), 7.08 (m, 2H), 6.49 (m, 3H); 13C NMR
(400 MHz; DMSO-d6), δ, ppm: 148.6, 147.1, 142.9 (2C),
141.6, 140.5, 139.2, 138.4, 136.1, 135.8, 133.4, 130.8
(2C), 129.4, 128.7, 125.9, 125.2, 119.7; Anal. Calcd for
C22H13ClFN3 (373): C, 70.69; H, 3.51; N, 11.24; Found:
C, 70.83; H, 3.26; N, 11.38.
General procedure for the synthesis of 9-(4-chlorophenyl)-
6-phenyl imidazo[1,2-a][1,8]naphthyridine derivatives (5a–
g).
To take compound 3-phenyl-1,8-naphthyridin-2-
amine 3 (1 mmol), 2-bromo-1-(4-chlorophenyl)ethan-1-
one 4 (1 mmol) and added catalyst DABCO 10 mol %
(11.2 mg) in water (5 mL) were ground in a mortar and
pestle for the specified time indicated in Table 1. After
completion of the reaction (monitored by the TLC), the
reaction mixture was poured into cold water. The solid
found was filtered, washed with water, recrystallized from
methanol, and obtained analytically pure products.
6-(4-bromophenyl)-9-(4-chlorophenyl) imidazo[1,2-a][1,8]
naphthyridine (5c).
White compound; IR (KBr) (λmax,
cmÀ1): 1648 (C═C), 1602, (C═N), 839 (C─Cl); 1H
NMR (400 MHz; DMSO-d6), δ, ppm: 8.73 (s, 1H), 8.21
(d, 2H, J = 7.8 Hz), 7.96 (d, 2H, J = 7.2 Hz), 7.38–7.97
(m, 8H); 13C NMR (400 MHz; DMSO-d6), δ, ppm:
148.9, 147.5, 145.1 (2C), 144.6, 143.2, 138.6, 137.3,
136.4 (2C), 134.7, 133.9, 132.4, 131.2, 128.5, 127.8,
126.2, 125.6 (2C), 121.6, 116.8; Anal. Calcd for
C22H13BrClN3 (434): C, 60.78; H, 3.01; N, 9.67; Found:
C, 60.53; H, 3.17; N, 9.74.
General procedure for the synthesis of 3-(6-phenyl
imidazo[1,2-a][1,8]naphthyridin-9-yl)-2H-chromen-2-one
derivatives (7a–f).
The mixture of the appropriate 3-
phenyl-1,8-naphthyridin-2-amine (1 mmol), 3-(2-
3
bromoacetyl)-2H–chromen-2-one 6 (1 mmol), and added
DABCO (10 mol %) (11.2 mg) in water (5 mL) was
ground by mortar and pestle. On completion of the reaction
(monitored by TLC), the mixture was poured into ice cold
water, and then the resulting solid product was filtered,
washed with water, and purified by recrystallization from
methanol to furnish corresponding compounds (7a–f).
9-(4-chlorophenyl)-6-(3-nitrophenyl)
naphthyridine (5d). Brown compound; IR (KBr) (λmax
cmÀ1): 1652 (C═C), 1608, (C═N), 841 (C─Cl); 1H
imidazo[1,2-a][1,8]
,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Banoth, S. Perugu, and S. Boda
Vol 000
NMR (400 MHz; DMSO-d6), δ, ppm: 8.62 (s, 1H), 8.51 (d,
2H, J = 7.6 Hz), 8.32 (d, 2H, J = 7.2 Hz), 7.96 (m, 5H),
7.38–7.97 (m, 3H); 13C NMR (400 MHz; DMSO-d6), δ,
ppm: 149.3, 148.7, 146.3 (2C), 144.8, 142.5, 139.1,
138.8, 135.6, 134.3 (2C), 133.4, 132.6, 129.3, 128.4,
127.3, 126.7, 125.9, 122.2, 118.5; Anal. Calcd for
C22H13ClN4O2C (400): C, 65.93; H, 3.27; N, 13.98;
(C─O─C); 1H NMR (400 MHz; DMSO-d6), δ, ppm:
8.91 (s, 1H), 8.27 (d, 2H, J = 7.2 Hz), 7.96–7.82 (m,
6H), 7.72 (m, 5H); 13C NMR (400 MHz; DMSO-d6), δ,
ppm: 161.2, 154.2, 148.6, 147.2, 143.7 (2C), 139.4,
137.2, 134.3, 129.6, 129.2 (2C), 127.9, 127.5, 120.4
(2C), 117.5, 116.3; Anal. Calcd for C25H14FN3O2
(407.40): C, 73.70; H, 3.46; N, 10.31; Found: C, 73.57;
Found: C, 65.67; H, 3.41; N, 13.76.
3-(9-(4-chlorophenyl)imidazo[1,2-a][1,8]naphthyridin-6-yl)
H, 3.62; N, 10.49.
3-(6-(4-bromophenyl) imidazo[1,2-a][1,8]naphthyridin-9-yl)-
phenol (5e). Pale yellow compound; IR (KBr) (λmax
,
2H-chromen-2-one (7c).
Brown compound; IR (KBr)
cmÀ1): 1656 (C═C), 1608, (C═N), 833 (C─Cl); 1H
NMR (400 MHz; DMSO-d6), δ, ppm: 9.87 (s, 1H),
8.19 (d, 2H, J = 7.2 Hz), 7.98 (m, 6H), 7.83 (d, 2H,
J = 7.2 Hz), 6.95 (m, 3H); 13C NMR (400 MHz;
DMSO-d6), δ, ppm: 144.9, 143.7, 142.6, 140.3, 139.7,
138.5, 136.8 (2C), 134.6, 133.6, 132.3 (2C), 129.5,
128.3, 127.4, 126.9, 125.3 (2C), 120.7, 114.8; Anal.
Calcd for C22H14ClN3O (371.82): C, 71.07; H, 3.80;
N, 11.30; Found: C, 71.23; H, 3.96; N, 11.54.
(λmax, cmÀ1): 1722 (lactone, C=O), 1678 (C=C), 1221
1
(C–O–C); H NMR (400 MHz; DMSO-d6), δ, ppm: 8.58
(s, 1H), 8.26 (m, 4H), 7.96 (d, 2H, J = 7.2 Hz), 7.89–
7.56 (m, 7H); 13C NMR (400 MHz; DMSO-d6), δ, ppm:
160.3, 153.7, 149.3, 147.4 (2C), 141.7, 139.7, 135.4
(2C), 132.9, 129.2 (2C), 129.0, 127.5, 121.6 (2C), 117.3,
116.5; Anal. Calcd for C25H14BrN3O2 (468.31): C, 64.12;
H, 3.01; N, 8.97; Found: C, 64.06; H, 3.23; N, 8.82.
3-(6-(3-nitrophenyl) imidazo[1,2-a][1,8]naphthyridin-9-yl)-
2H-chromen-2-one (7d).
Light brown compound; IR
9-(4-chlorophenyl)-6-(4-nitrophenyl)
imidazo[1,2-a][1,8]
(KBr) (λmax, cmÀ1): 1723 (lactone, C═O), 1672 (C═C),
1220 (C─O─C); 1H NMR (400 MHz; DMSO-d6), δ,
ppm: 8.69 (s, 1H), 8.36 (d, J = 7.2 Hz, 2H), 7.94 (m,
6H), 7.21 (d, J = 6.8 Hz, 2H), 7.18–7.06 (m, 3H); 13C
NMR (400 MHz; DMSO-d6), δ, ppm: 161.2, 153.5,
149.1, 147.6, 142.4 (2C), 139.6, 136.7, 135.6 (2C),
129.4, 129.0 (2C), 128.9, 127.6, 119.2 (2C), 117.4,
115.1; Anal. Calcd for C25H14N4O4 (434.41): C, 69.12;
naphthyridine (5f).
White compound; IR (KBr) (λmax
,
cmÀ1): 1653 (C═C), 1609, (C═N), 837 (C─Cl); 1H
NMR (400 MHz; DMSO-d6), δ, ppm: 8.83 (m, 3H), 8.27
(s, 1H), 7.96 (m, 3H), 7.83 (d, 2H), 7.32–7.27 (m, 3H),
6.72 (s, 1H); 13C NMR (400 MHz; DMSO-d6), δ, ppm:
149.6, 148.3, 147.5, 145.2, 143.5 (2C), 140.7, 139.6,
137.4, 136.3, 134.4, 132.2 (2C), 129.8, 129.2, 128.4,
127.6, 125.3, 123.6, 119.7; Anal. Calcd for
C22H13ClN4O2 (400.82): C, 65.93; H, 3.27; N, 13.98;
Found: C, 65.82; H, 3.46; N, 13.86.
H, 3.25; N, 12.90; Found: C, 69.34; H, 3.14; N, 12.76.
3-(6-(3-hydroxyphenyl) imidazo[1,2-a][1,8]naphthyridin-9-
yl)-2H-chromen-2-one (7e).
Light brown compound; IR
6-(3-chlorophenyl)-9-(4-chlorophenyl) imidazo[1,2-a][1,8]
(KBr) (λmax, cmÀ1): 3336 (OH), 1724 (lactone, C═O),
1602 (C═N), 1205 (C─O─C); 1H NMR (400 MHz;
DMSO-d6), δ, ppm: 9.34 (s, 1H), 8.87 (d, 2H,
J = 7.2 Hz), 8.15 (m, 3H), 7.96 (m, 4H), 7.21–7.09
(m, 4H); 13C NMR (400 MHz; DMSO-d6), δ, ppm:
160.4, 153.2, 148.9 (2C), 147.4, 141.3 (2C), 139.7,
138.2, 136.2, 129.4 (2C), 128.9, 128.8 (2C), 128.1,
118.6, 117.3, 116.8; Anal. Calcd for C25H15N3O3
(405.41): C, 74.07; H, 3.73; N, 10.36; Found: C, 74.26;
naphthyridine (5g). Yellow compound; IR (KBr) (λmax
,
cmÀ1): 1655 (C═C), 1607, (C═N), 842 (C─Cl); 1H
NMR (400 MHz; DMSO-d6), δ, ppm: 8.58 (s, 1H), 8.34
(d, 2H, J = 7.2 Hz), 8.13 (s, 1H), 7.96 (d, 2H,
J = 7.2 Hz), 7.38–7.97 (m, 7H); 13C NMR (400 MHz;
DMSO-d6), δ, ppm: 148.7, 147.5 (2C), 146.5, 145.7
(2C), 144.5, 142.7, 139.5, 138.2, 136.4, 135.1 (2C),
131.7, 129.4, 128.8, 127.9, 126.6, 125.4, 122.7 (2C),
118.5; Anal. Calcd for C22H13Cl2N3 (390.27): C, 67.71;
H, 3.36; N, 10.77; Found: C, 67.59; H, 3.45; N, 10.83.
H, 3.56; N, 10.48.
3-(6-(4-nitrophenyl) imidazo[1,2-a][1,8]naphthyridin-9-yl)-
3-(6-phenyl
imidazo[1,2-a][1,8]naphthyridin-9-yl)-2H-
2H-chromen-2-one (7f).
Brown compound; IR (KBr)
chromen-2-one (7a).
Pale yellow compound; IR (KBr)
(λmax, cmÀ1): 1724 (lactone, C═O), 1671 (C═C), 1222
(C─O─C); 1H NMR (400 MHz; DMSO-d6), δ, ppm:
9.06 (s, 1H), 8.47 (m, 3H), 8.06 (m, 5H), 7.87 (d, 2H,
J = 7.2 Hz), 7.31–7.23 (m, 3H); 13C NMR (400 MHz;
DMSO-d6), δ, ppm: 161.4, 152.4, 147.5, 147.6 (2C),
141.3, 139.7, 137.4, 134.7 (2C), 129.3, 128.7, 128.3
(2C), 127.6, 117.6, 116.4, 116.4; Anal. Calcd for
C25H14N4O4 (434.41): C, 69.12; H, 3.25; N, 12.90;
Found: C, 69.26; H, 3.17; N, 12.76.
(λmax, cmÀ1): 1720 (lactone, C═O), 1680 (C═C), 1224
(C─O─C); 1H NMR (400 MHz; DMSO-d6), δ, ppm:
9.17 (s, 1H), 8.47 (m, 4H), 7.51 (d, 2H, J = 7.2 Hz),
7.27.05 (m, 5H), 6.98 (d, 2H, J = 6.8 Hz), 6.04 (s, 1H);
13C NMR (400 MHz; DMSO-d6), δ, ppm: 161.9, 153.4
(2C), 148.3, 146.5, 143.6, 138.7 (2C), 136.3, 133.5 (2C),
129.8, 129.5 (2C), 127.8, 127.5, 119.6, 116.5, 115.9;
Anal. Calcd for C25H15N3O2 (389.41): C, 77.11; H, 3.88;
N, 10.79; Found: C, 77.26; H, 3.97; N, 10.68.
3-(6-(4-fluorophenyl) imidazo[1,2-a][1,8]naphthyridin-9-yl)-
Biological
evaluation
(antimicrobial
activity).
2H-chromen-2-one (7b).
White compound; IR (KBr)
Antibacterial activity. All the newly synthesized
compounds (5a–g, 7a–f) were evaluated for their in vitro
(λmax, cmÀ1): 1724 (lactone, C═O), 1676 (C═C), 1223
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Green Synthesis of Fused Imidazo[1,2-a][1,8]naphthyridine Derivatives and Their
Biological Evaluation
antibacterial activity against the Gram-positive bacteria
Staphylococcus aureus and Gram-negative bacteria
Escherichia coli at three different concentrations using
standard reference drug Penicillin. The activity was
determined by agar well diffusion technique according to
the literature procedure [24]. These entire compounds
demonstrate good inhibition activity. Especially,
compounds 7e, 7d, and 5d demonstrated high
antibacterial activity against all the tested strains as
shown in Table 2.
Antifungal activity. All these synthesized compounds
(5a–g, 7a–f) were evaluated for their antifungal activity
against the two pathogenic fungal strains Aspergillus niger
and Candida metapsilosis utilizing standard reference drug
Griseofulvin. The activity was resolved by using the disc
diffusion technique [25]. All these compounds shown good
inhibition activity against the tested pathogenic fungal
strains among them products 5c, 7c, and 7f showed
appreciable activity while the compounds 7e, 7d, and 5d
exhibited excellent antifungal activity shown in Table 2.
Table 2
Antimicrobial evaluation data of the novel imidazo[1,2-a][1,8]naphthyridines.
Zone of inhibition of compounds (5a–g, 7a–f) in (mm)
Bacterial strains
Fungal strains
Staphylococcus aureus
Escherichia coli
Aspergillus niger
Candida metapsilosis
(Conc. in μg/mL)
(Conc. in μg/mL)
(Conc. in μg/mL)
(Conc. in μg/mL)
Compounds
5a
5b
5c
5d
5e
5f
5g
7a
7b
7c
7d
7e
7f
10
25
35
10
25
35
10
26
35
10
26
35
6
5
4
8
8
5
7
7
5
6
8
9
6
9
16
17
16
19
8
14
16
18
16
18
19
20
19
24
26
23
22
29
11
24
20
31
23
31
31
33
28
34
7
6
5
8
6
6
6
8
6
8
8
8
7
9
18
19
17
20
9
19
17
2
17
2
2
21
19
25
25
26
25
30
10
26
27
32
21
32
32
33
26
34
6
7
6
7
8
5
6
8
5
8
8
9
6
-
10
20
19
17
20
10
18
17
17
15
17
17
21
17
-
25
24
26
29
12
26
25
28
23
28
28
30
25
-
5
7
6
7
7
6
5
7
6
7
7
8
7
-
10
19
16
19
21
18
18
15
15
16
15
20
22
17
-
27
26
25
28
26
21
23
25
24
26
29
31
27
-
Penicillin
Griseofulvin
-
-
-
-
-
-
24
33
23
34
Compounds that show more activity are shown in bold font.
Table 3
Phosphoinositide-dependent protein kinase-1 (PDK-1) molecular interactions.
Receptor and its atoms involved
Ligand
in interactions (PDK-1)
Interacting atoms
H-bond distance in (A°)
Docking energy (Kcal/Mol)
5c
ALA259-O
LYS257-O
ARG204-NH1
ALA259-O
VAL229-NH
LYS257-O
ALA259-O
ARG196-NH1
ILE202-NH
ALA259-O
LYS257-O
ALA259-O
PHE142HE2
LEU230-NH
LYS257-O
12 NH2
18 NH2
30 O
13 NH2
28 NH2
18 NH2
18 NH2
1O
3.13
2.99
2.63
3.00
3.30
2.97
3.25
3.07
1.59
3.09
2.95
3.15
1.46
2.81
2.88
3.31
À86.202
5d
7c
À79.507
À74.806
7d
7e
12 0
À78.019
À71.133
18 NH2
18 NH2
18 NH2
36O
9 O
18 NH2
18 NH2
7f
À82.583
ALA259-O
Compounds that show more activity are shown in bold font.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Banoth, S. Perugu, and S. Boda
Vol 000
Figure 2. Binding mode of the phosphoinositide-dependent protein kinase-1 and 7e molecule. [Color figure can be viewed at wileyonlinelibrary.com]
Molecular docking studies.
Crystal structure of
the structure, and these are used for docking using the
ligand fit module provided by acceleries, and obtained
results were scrutinized based on the highest dock score
and number of H-bond interactions. All these ligands
were docked in Ligand fit module and molecular
interactions of docking complex of PDK-1, and these
ligands interactions showed were listed in the Table 3. In
docking interactions, 5c structures two hydrogen bonds
with ALA259 and LYS257 with 3.13 and 2.99 Ao bond
lengths, respectively; the binding site residue, ALA259
phosphoinositide-dependent protein kinase-1 (PDK-1)
was obtained from the protein data bank (3H9O) [26] and
imported into Discovery studio 2.5. Crystallized water
molecules were removed, and polar hydrogen was added
to the complex structure, and 3H9O was applied CHARM
force field, and minimizations were performed until the
average root mean square deviation of the non-hydrogen
atoms reached 0.3 Ao. A grid (10 × 10 × 10 Ao) was
generated around the centroid of the phosphoinositide
within 4 Å. Furthermore, we identified the binding sites in
Figure 4. Molecular docking interactions of phosphoinositide-dependent
protein kinase-1 with our synthesized molecule 5d. [Color figure can be
viewed at wileyonlinelibrary.com]
Figure 3. Binding mode of phosphoinositide-dependent protein kinase-1
and 7d molecule. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Green Synthesis of Fused Imidazo[1,2-a][1,8]naphthyridine Derivatives and Their
Biological Evaluation
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and LYS257 of PDK-1, was involved in п–п interaction
with all ligands. 7d structures ILE202 and ALA259 with
1.59 and 3.09 Ao, respectively, 7f structures three
hydrogen bonds with LEU230, LYS257, and ALA259
with 2.81, 2.88, and 3.31 Ao, respectively, and 7e
structures two hydrogen bonds with LYS257 and ALA259
with 2.95 and 3.15 Ao, respectively. All these compounds
shown better molecular bonding interactions. Among
them 5c, 5d, 5g, 7d,7e, 7f involved in intermolecular
hydrogen bonding with low distance and Vander Waal
contacts. Among the all compounds (5a–g, 7a–f), the
most active 7e, 7d, and 5d interacting receptors are
exposed in Figures 2, 3, and 4.
CONCLUSIONS
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In conclusion, we have developed an efficient,
convenient, environmentally friendly, economically
viable, high yielding, and cleaner methodology for the
construction of fused imidazo[1,2-a][1,8]naphthyridine
derivatives using DABCO catalyst ground by mortar
pestle. The significant advantages of this procedure are
operational simplicity, short reaction times, and excellent
purity of the products. Further, we found that the solid
state reactions proceed much faster and more efficiently
than the solution phase reactions, probably because the
solid state reaction is a very high concentration reaction.
The antimicrobial activity of the synthesized compounds
was assessed against pathogenic bacterial and fungal
strains and compounds 7e, 7d, and 5d exhibited the
highest activity. Moreover, in silico molecular docking
studies results have proved that strong binding affinity
and more H-bonds interaction.
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SUPPORTING INFORMATION
Additional Supporting Information may be found online
in the supporting information tab for this article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet