Synthesis of Naphthalene based Quinoxaline derivatives using surfactant and their biological applications as drugs

Article abstract of DOI:10.13005/ojc/330430

One pot synthesis of Naphtaleno-4, 6-(2, 4-quinoxaline) derivatives were achieved using direct coupling reaction by retaining 2,3-diaminonaphthalene as common with different forms of diketones viz., Benzil, 4, 4'-dimethyl benzil and 4, 4'-difluoro benzil.

Full text of DOI:10.13005/ojc/330430

ISSN: 0970-020 X
CODEN: OJCHEG
2017, Vol. 33, No. (4):
Pg.1856-1863
ORIENTAL JOURNAL OF CHEMISTRY
An International Open Free Access, Peer Reviewed Research Journal
www.orientjchem.org
Synthesis of Naphthalene based Quinoxaline derivatives
using surfactant and their biological applications as drugs
GOvINdARAJ CHINNASAMY1*, KULLAGOUNdER SUbRAMANI2,
vENKATESAN SRINIvASAN3
1Research Scholar, Department of Chemistry, Manonmaniam Sundaranar University,
Tirunelveli, Tamilnadu, India.
2Department of Chemistry, Islamiah College, Vaniyambadi, Tamilnadu, 635752, India.
3Department of Chemistry, Adhiyamaan College of Engineering, Hosur,
Tamilnadu, 635109, India.
*Corresponding author E-mail: gshchemistry@gmail.com
http://dx.doi.org/10.13005/ojc/330430
(Received: August 15, 2016; Accepted: December 12, 2016)
AbSTRACT
One pot synthesis of Naphtaleno-4, 6-(2, 4-quinoxaline) derivatives were achieved using
direct coupling reaction by retaining 2,3-diaminonaphthalene as common with different forms of
diketones viz., Benzil, 4, 4'-dimethyl benzil and 4, 4'-difluoro benzil. The synthesis was carried out
using CTAB and polymer supported sulphanilic acid, independently. The use of 4, 4'-difluoro benzil
was found to be better than 4, 4'-dimethyl benzils, in terms of the % yield and the time consumption.
Results confirmed that the use of CTAB was superior to the sulphanilic acid in the majority of aspects.
Quinoxaline derivatives, so obtained, were independently used for the biological study to determine
their efficiency in mice for anxiolytic, sedative and hypnotic activity. It was learned from the results
that the Naphtaleno-4, 6-(2, 4-quinoxaline) derivatives were far better than their standard Diazepam
in sedative and hypnotic activity.However, the efficiency was comparatively lesser than Diazepam in
anxiolytic activity. In most cases, Fluoro substituted Diazepine show deviation in activity.The results
of locomotor activity suggest the appreciable alertness of the mice when exposed to naphthalene
based quinoxaline drugs.
Keywords: Quinoxaline derivatives, CTAB, sulphanilic acid, anxiolytic,
sedative, hypnotic.
INTROdUCTION
suit a broad spectrum of biological and medicinal
interest. Their applications do not end with the
disease curing drugs, but also extends as industrially
useful elements like dyes and electro-luminescent
materials.
Quinoxalines have been extensively
synthesized for their ability to antibiotic, antiviral,
anti-carcinogenic and antibacterial and the like
medicinal properties. Their derivatives are found to

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CHINNASAMy et al., Orient. J. Chem., Vol. 33(4), 1856-1863 (2017)
Research has been currently made to forms namely, benzil, 4,4’-dimethylbenzil and 4,4’-
increase the yield, efficiency and to decrease the diflurobenzil for the purpose of finding the substituent
timing, cost of these highly wanted drugs. Several effect. CTAB was used as the cationic surfactant. A
promoters, catalysts and surfactants have been mixture of 1M HCl and Ethanol-spirit was used as
employed in this regard.The most common precursor the solvent. After the reaction completion (which
viz., o-Phenyline diamine and their substituted was completely monitored by TLC), the synthesized
derivatives are known. In general, quinoxalines product was precipitated by using Ethanol.Surfactant
are synthesized by the simple condensation of (CTAB) was left in the solvent without further
Naphthalene 2, 3-diamines with benzil compounds actions.
by the formation of C-C and carbon-heteroatom1
using CTAB as the surfactant.This is one of the well procedure for the synthesis of derivatives
known ways for developing green synthetic routes.
In a 100 ml beaker, 2 mmol of Benzil, 2
1, 2-diketones appear frequently as substituted mmol of CTAB were added to 10 ml Ethanol and
by condensation of aryl-1, 2-diamines with benzil placed on a magnetic stirrer cum temperature
0
compounds.
bath at stirring speed of 750 rpm at 35 C, a little
higher than room temperature. A mixture of 10 ml
The preparation of Quinoxaline by the of 2, 3-diaminonapthalene dissolved in 1M HCl was
reaction of benzils and their derivatives with added in-situ to this reaction mixture drop by drop. A
Naphthalene based diamines uses surfactant pale brown coloured precipitate was obtained after
property and hence, CTAB was considered as the 10 minutes. The precipitate was filtered using
surfactant medium for the reaction2. In order to find Whatmann 40 filter paper and subsequently dried
other competing catalyst that may be better than under shadow. The precipitate was re-crystallized
CTAB, in this paper, we compared the efficiency with ethanol. This re-crystallized yield was used as
of the same synthesis with that of the polymer a source for furtherTLC and HPLC chromatographic
supported sulphanilic acid3.The resulting quinoxaline studies followed by spectroscopic characterization.
products were verified for their biological applications The structure of the resulting compound was as
such as anxiolytic, sedative and hypnotic activities shown in the Figure 1.
on mice.
procedure for the synthesis of 2, 3-diphenyl
MATERIALS ANd ExpERIMENTAL METHOdS
benzo [g] quinoxaline
In a 100 ml beaker, 2 mmol of 1,2-diphenyl-
ethane-benzil, 2 mmol of CTAB were added to 10 ml
Chemistry
Melting point of the resulting products Ethanol and placed on magnetic stirrer, added with 2
were determined using a capillary in a melting point mmol of 2,3-diaminonaphthalene in 10 ml 1M HCl,
apparatus (Toshiba) and are noted as such. The in-situ to this reaction mixture, drop by drop. The
FTIR Spectra were recorded on a Perkin Elmer precipitate was re-crystallized with ethanol.
Spectrum1 FT-IR instrument with the resolution
of 1.0 cm-1 using the KBr disc in the range of
X
6
4000-400 cm-1. The PMR and CMR spectra were
1
5
4
measured on a Bruker Advance III instrument (600
and 150 MHz, respectively) using a solvent signal
as the reference. The units of Chemical shifts (d)
are given in ppm and coupling constants (J) in Hz.
Assignments of signals in CMR spectra were made
on the basis of the HMQC experiments.
9
11
2
N
N
8
10
7
12
3
3'
12'
8'
10'
7'
4'
11'
9'
2
1
5'
6'
X
Both 2,3-diaminonapthalene (99.9%),
1,2-diketones (99.8%) were obtained from Sigma-
Aldrich, India and were used as such without further
purification. 1,2-diketone was used in three different
Fig. 1: Structural formula of 2,3-
diphenylbenzo(g)quinoxaline [x = H or -M or
+M group]

CHINNASAMy et al., Orient. J. Chem., Vol. 33(4), 1856-1863 (2017)
1858
Characterization of 2, 3-diphenyl benzo [g]
quinoxaline
Characterization of 2, 3-bis(4-fluorophenyl)
benzo[g]quinoxaline
yield= 97%: Pale Brown coloured crystals:
m.p. = 99°C; FTIR: Heterocyclic -C=N & -C=C-
str.=1595.13 cm-1, aromatic –CH str.=3061.03 cm-1,
aromatic –C=C- str.=1666.50 cm-1, aromatic –C-C-
str.=1517.98 cm-1, aromatic –C-N- str. = 1325.10
cm-1; H1NMR : (400 MHz, DMSO): d = 7.946–7.925
(J = 1.9622) (t, 2H, arom.); d =7.829-7.791 (J =
1.000) (t, 2H, arom.);d = 7.660-7.621 (J = 2.0311) (t,
4H, arom.); C13NMR: (400 MHz, DMSO) d = 194.79,
135.50, 132.25, 129.66, 129.56, 129.48, 128.39,
128.01, 127.11, 40.18, 39.97, 39.76, 39.55, 39.34,
39.14, 38.93 ppm.
yield = 98%:Pale Brown coloured crystals.
m.p.= 118°C; FTIR: Heterocyclic -C=N & -C=C- str.
= 1597.06 cm-1, aromatic –C-H str. = 3074.53 cm-1,
aromatic –C=C- str. = 1666.50 cm-1, aromatic –C-C-
str. = 1506.41 cm-1, aromatic –C-N str.=1317.38
cm-1, C-F bond = 1101.35 cm-1; H1NMR (400 MHz,
DMSO) d = 8.072-8.021 (J=2.00) (m, 8H, arom.);
d = 7.497 - 7.439 (J = 2.0417) (m, 6H, arom.);
C13NMR (400 MHz, DMSO) d = 192.60, 167.51,
164.97, 133.06, 132.96, 128.99, 128.97, 116.86,
116.64, 40.11, 39.91, 39.70, 39.49, 39.28, 39.07,
38.86.
procedure for the synthesis of 2, 3-bis(4-
methylphenyl)benzo[g]quinoxaline
pharmacology
Animal subject used
In a 100 ml beaker, 2 mmol of 4,4’-
Swiss albino mice of male gender (21–24 g)
were used throughout the study.They were provided
normal pellet diet and drinking water ad libitum and
were exposed to 12 h sunlight and 12 h dark cycle.
The animals were made physiologically responsive
to the laboratory conditions prior to the experiments.
Animals’ care was taken as per guidelines of
the Committee for the Purpose of Control and
Supervision of Experiments on Animals (CPCSEA),
Environment and Forests Ministry, India.
dimethylbenzil, 2 mmol of CTAB were added to 10
ml Ethanol and placed on magnetic stirrer, added
with 2 mmol of 2,3-diaminoNapthalene in 10ml 1M
HCl, in-situ to this reaction mixture, drop by drop.
The precipitate was re-crystallized with Ethanol.
Characterization of 2, 3-bis(4-methylphenyl)
benzo[g]quinoxaline
yield = 95%:Pale Brown coloured crystals:
M.P. =107°C; FTIR :Heterocyclic -C=N str. & -C=C-
str. =1595.13 cm-1, –C-H- str. in CH3 = 2922.16 cm-1,
aromatic C-H str.=3047.53 cm-1, aromatic –C-C- str.
= 1429.25 cm-1, aromatic –C=C- str.=1662.64 cm-1,
aromatic –C-N- str.=1313.52 cm-1, , in-plane bending
of –C-H- in CH3 = 1037.70 cm-1, out of plane bending
of –C-H- in CH3 =736.81 cm-1; H1NMR:(400 MHz,
DMSO) d = 7.809-7.788 (J=2.000) (d, 8H, arom.);
d =7.441-7.420 (J = 2.0416) (d, 6H, arom.); d
=2.414 (s, 3H, in -CH3) C13NMR: (400 MHz, DMSO)
d = 194.60, 146.44, 130.03, 129.95, 129.59, 40.18,
39.97, 39.76, 39.55, 39.34, 39.13, 38.92, 21.41
ppm.
drugs used
Diazepam hydrochloride (Ranbaxy
Laboratories, Gurgaon, India) was procured and
used as a standard drug and it was diluted with
saline water to the needed strength prior to the use.
The test compounds were suspended in 0.3% w/v
of sodium carboxymethyl cellulose (CMC) and were
administered through oral gavage.
Acute Toxicity Studies
Acute Oral Toxicity (AOT 423) guideline
was followed for the acute toxicity studies of the
synthesized compounds. Briefly, overnight fasted
animals were treated with various concentrations of
the compounds to be tested (5, 50, 300 and 2000
mg/kg, bw) by oral route.The observation of animals
for any behavioral changes or mortality for first
24 h was done. The animals were maintained for
another 14 days to check the abnormal changes and
mortality. Based on the results, the dose was fixed
for pharmacological studies.
procedure for the synthesis of 2, 3-bis(4-
fluorophenyl)benzo[g]quinoxaline
In a 100 ml beaker, 2 mmol of 4,4’-
difluorobenzil, 2 mmol of CTAB were added to
10 ml Ethanol and placed on magnetic stirrer, added
with 2 mmol of 2,3-diaminoNapthalene in 10 ml 1M
HCl, in-situ to this reaction mixture, drop by drop.The
precipitate was re-crystallized with Ethanol.

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CHINNASAMy et al., Orient. J. Chem., Vol. 33(4), 1856-1863 (2017)
Anxiolytic activity
Elevated plus Maze (EpM) Test
of the board. During these 5 minutes of test period,
number of head dips was observed.
To assess the anti-anxiety activity of test
compounds, elevated plus maze (EPM) was used4. procedure
Two open arms (16 × 5 cm) and two closed arms
Animals were broadly divided in to eleven
(16 × 5 × 12 cm) having an open roof, with the groups, each 6 in a group. The Group I served as
plus-maze elevated (25 cm) from the floor was the control served with the vehicle, Group II served
set up. Each mouse was individually placed at the as standard served with diazepam drug at the
centre of the EPM with its head facing exactly the dose of 3 mg/kg. Group III - XI the animals were
open arms. This experiment lasts 5 minutes, during treated with the test compounds at the dose of
which behavior of the mouse was recorded as: (a) (5 mg/kg, bw, p.o).The compounds to be tested were
the number of entries of drug into the open arms, introduced orally using a tuberculin syringe fitted with
(b) mean time spent by the mouse in the open arms oral canula. After 45 minutes of oral administration
(mean time or average time = total time spent in open of the test compounds, the animals were placed in
arms/number of entries in arms).
to the center of the perforated board and noted for
the period of 5 minutes and the number of head
exploration was counted in order to find out the
procedure
Animals were divided in to 11 groups, each sedative and hypnotic activity.
6 in a group. The Group I served as control served
with vehicle, Group II served as standard served Locomotor activity
with diazepam at the dose of 0.5mg/kg. Group
To evaluate the spontaneous locomotor
III - XI the animals were treated with the compounds activityofthesynthesizedcompounds,actophotometer
to be tested at the dose of (5 mg/kg, bw, p.o). The was used.Actophotometer (PopularTraders, Ambala,
compounds were administered through oral way India) was utilized for the present study. Mice were
using a tuberculin syringe fitted with oral canula. placed separately in activity cage for 5 minutes test
The drug administration schedule was adjusted so period, 45 minutes after the introduction of test drugs.
that each mouse was having its turn on the EPM Locomotor activity was noted in terms of the activity
apparatus 45 minutes after the administration of scores.
the dose. During the complete experiment, all the
animals were allowed to socialize. Every care was procedure
taken to make sure that no external stimuli, other than
Animals were divided in to 11 groups, each
the height of plus-maze could invoke anxiety in the group consists of 6 animals. The Group I served as
animals. The parameters noted is (a). Time spent in control served with vehicle, Group II animals served
open arm and (b). Number of arm entries to assess as standard which receives diazepam at the dose of
the anxiolytic activity.
3 mg/kg, through intra-peritoneal route.Group III - XI
the animals were treated with the test compounds at
the dose of (5 mg/kg, bw, p.o). The test compounds
were administered orally by the use of a tuberculin
Sedative and Hypnotic activity
Hole - board Test
In order to examine the sedative and syringe fitted with oral canula. After 45 minutes of
hypnotic activity of the synthesized compounds, oral introduction of the various fractions the animals
Hole-Board Test was performed. The Hole-board were placed in to the actophotometer. Movement of
apparatus is set to comprise a grey Perspex panel the animal is recorded by the light beams present
(40×40 cm, 2.2 cm thick) with 16 equidistant holes inside the actophotometer for the evaluation of the
(diameter of 3 cm) in the floor. Photocells below the locomotor activity.
surface of the holes have given way for the measure
of the number of head dips. The board was placed
15 cm above the table and it was divided with black
RESULTS ANd dISCUSSION
water-resistant marker into 9 squares of 10×10 cm. Synthesis and Characterizations
30 minutes after the introduction of the test drug;
Condensation of 2, 3-diaminonapthalene
each mouse was separately placed in the centre with benzil was employed as the key reaction. The

CHINNASAMy et al., Orient. J. Chem., Vol. 33(4), 1856-1863 (2017)
effect of para substituent present on was verified Anxiolytic activity
1860
by varying different types of groups (such as
electron donating and electron withdrawing) and the
corresponding results are mentioned in table 1.From
the results, the electron withdrawing substituent
such as -Fluro, yield (Scheme III) was better than
the electron donating groups such as -Methyl,
(Scheme II).
Synthesis of aromatic condensed
naphthoxazinone derivatives has received
considerable attention because of their broad
spectrum of biological properties7.Only compounds
such as Quinoxaline diones and their derivatives
effect by stimulating low index of open arm avoidance
in mouse in an EPM test model of Anxiolytic
activity. Compounds such as Sulphanilamide based
quinoxaline and their derivatives show anxiolytic
effect in mouse that was superior to the effect
product by diazepam while the compound such as
quinoxaline diones show anxiolytic effect comparable
to diazepam8. Some simple 2,3-quinoxaline diones
containing +I and –I groups and two quinoxalinone
only one carbonyl functional group has synthesized
and screened for neuro-pharmacological activity in
mice and rats9. Only the c
The method for the synthesis of
2-substitute benzothiazoles from the reaction of
2-aminothiophenol with aldehyde catalysed by
CTAB in water5 was followed. One step synthesis
of mesoporous material was achieved by adopting
the double templates consisting of the conventional
cation hyamine surfactant CTAB6.
Acute Toxicity Studies
Oral toxicity study for the test compounds
were determined as per AOT 423 guidelines.Two out
of three animals were died in the group of animals
treated with 300 mg/kg, bw, hence the preceding
dose was considered as LD50 dose.A dilute quantity
of drug i.e., one tenth of the dose(5 mg/kg, bw) was
used for further studies.
hloro- functional group at position 6 and N,
N-dibenzylsulphonamido group are essential for
neuro-production against the induced seizers,
in addition to the observed good activity of the
dibenzylsulfonamido quinoxaline diones.
The time spent by the animals in the open
Table 1: Reaction schemes
benzil
pyrimidine
Qunioxaline
Scheme
NH2
NH2
O
O
N
N
BEN
(I)
NH2
NH2
O
O
N
N
BEN-Me
(II)
NH2
NH2
O
O
N
N
BEN-F
(III)

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CHINNASAMy et al., Orient. J. Chem., Vol. 33(4), 1856-1863 (2017)
arms treated with standard drug diazepam and the noted anxiolytic activity of the test compounds.
test compounds was significantly increased when Quinoxalines act not just by substituting for GABAA,
compared to the control group which was treated which bind at the á-subunit, but also increase the
with the same volume of vehicle. Among the test number of channel opening events, which leads to
compounds, all the three substituted quinoxaline an increase in conductance of Chloride ion and also
series showed significant anxiolytic activity, which inhibition of the action potential10.
shows mild to moderate activity. These compounds
show a little difference when compared to the Sedative and Hypnotic activity
standard drug which indicates that the compounds
The hole-board test used to assess
are equipotent anxiolytic to the standard diazepam. the sedative and hypnotic potential of the test
The results are depicted in the figures 2a and 2b.
compounds. This test confirmed the CNS calming
nature of the test compounds.The results are shown
It can be observed from the Figure 2a that in the Figure 3. The number of hole explore was
the time spent in open arm is increased nearer to counted for the period of 5 minutes and the results
the standard diazepam. Using the Figure 2b, the revealed that the control animal was active whereas
gradual increase in number of arm entries based on the head exploration has been largely reduced in the
the potency of the individual test compounds, can animals treated with the standard diazepam drug at
be witnessed. It should be noted that the increase in the dose of 4 mg/kg. The test compounds possess
open arm entry data is the most important index of various degree of hole exploration values.Diazepam
anxiolytic activity.Time spent on the central platform is the CNS depressant used in the management of
appears to be relevant to decision making process sleep disorders such as insomnia; these drugs have
and risk assessment process, further, the total arm a binding site on GABA receptor type-A ionophore
entries is the direct measure reflecting the changes complex (GABAA). The drug decreases activity,
in anxiety. The enhanced activity of the quinoxaline moderates excitement and calms the nerve recipient.
drug and its derivatives is expected to be due to the GABAergic pathway, since its transmission can
binding site of the ion channel receptor present in produce profound sleeping in mice. The ordinary
the CNS.This in turn, would stimulate the binding of inhibitory action of GABA consists in the opening
GABAA subunit with the GABA receptor, which would of chloride channels to allow hyperpolarizing the
produce the prolongation of opening of the channels membrane, leading to CNS depression and results in
of chloride ion.The prolonged opening leads to mild sedative and hypnotic activity.Glutamate and GABA
hyper polarization which may be responsible for are quantitatively the most representative excitatory
Fig. 2a:Time spent in open arms; 2b.Entries in open arm [Standard diazepam 0.5mg/kg]
[values are expressed as Mean SEM; ap<0.001, bp<0.01 vs Control group; cp<0.001, dp<0.01,
ep<0.05 vs Std group; data were analyzed by using One way ANOvA followed by Tukey Kramer
Multiple comparison Test.]

CHINNASAMy et al., Orient. J. Chem., Vol. 33(4), 1856-1863 (2017)
1862
Fig. 3: Sedative and Hypnotic activity [STd
diazepam 3mg/kg]
Fig. 4: Locomotor activity [STd (diazepam
3mg/kg)]
[values are expressed as Mean SEM;
ap<0.001, bp<0.01 vs Control group; cp<0.001,
dp<0.01 vs Standard group; data were analyzed
by using One way ANOvA followed by Tukey
Kramer Multiple comparison Test.]
[values are expressed as Mean SEM;
ap<0.001, bp<0.05 vs Control group; cp<0.001vs
Standard group; data were analyzed by using
One way ANOvA followed by Tukey Kramer
Multiple comparison Test.]
and inhibitory neurotransmitters, respectively, in
the mammalian brain. Thus, receptors for these
two neurotransmitters are regarded as usual and
essential targets for psychotropic drugs.The activity
of the compound to be tested may be due to binding
with these receptors.
hypnotic drugs are expected to exhibit their action
through GABA.Therefore, it is possible that the test
compounds may act by direct activation of GABA
receptors by the test compounds. The increase in
efficiency of the natural brain chemical, GABAA, by
the quinoxaline based derivative is achieved along
with the decrease in excitability of neurons.
Locomotor activity
The mean score in locomotor activity,
CONCLUSIONS
before and after the treatment were measured
and are shown in the Figure 4. There are notable
difference observed in the mean score before
treatment with standard and the test compounds.
After the standard/test drug treatment, the mean
score for the diazepam treated group and the test
Quinoxaline derivatives treated, together appear
lesser active, when compared to the control
group. But the test compounds were observed to
show worthier statistics when compared to the
standard drug. The results revealed the significant
reduction in locomotor activity by the quinoxaline
based derivatives. Locomotor activity is believed
as an index of alertness and a reduction in that
is an indicative of sedative activity. GABA is the
important inhibitory neurotransmitter in the CNS and
different anxiolytic, muscle relaxant and sedative-
Naphthalene based Quinoxalines were
successfully synthesized with greater yield (96%)
and shorter duration (5 minutes) using CTAB as the
surfactant.The synthesis in the absence of cationic
surfactant resulted in poor yield and time consuming
(35% and 90 min).The solubility of this compound in
ethanol, suggests that this product can be used as
a challenging drug for the pathogens.The synthesis
of naphthalene-quinoxaline by this method produced
no harmful emissions. These provide a very good
option for non-toxic drug possessing anxiolytic,
sedative and hypnotic properties. When compared
with benzodiazepine drugs, these naphthalene
based quinoxaline drugs shows a little lower effective
as an anxiolytic drug and better effect as a sedative
and hypnotic.

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ACKNOwLEdGEMENTS
Manonmaniam Sundaranar University,Tirunelveli, for
extending permission, support and infrastructure.
Authors are grateful to their respective
institutions, where they are working, and
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