Ligand-based design, synthesis, and pharmacological evaluation of 3-methoxyquinoxalin-2-carboxamides as structurally novel serotonin type-3 receptor antagonists

Article abstract of DOI:10.1002/ardp.201200038

Employing a ligand-based approach, 3-methoxyquinoxalin-2-carboxamides were designed as serotonin type-3 (5-HT₃) receptor antagonists and synthesized from the starting material o-phenylenediamine in a sequence of reactions. The structures of the

Full text of DOI:10.1002/ardp.201200038

Arch. Pharm. Chem. Life Sci. 2012, 000, 1–8
1
Full Paper
Ligand-Based Design, Synthesis, and Pharmacological
Evaluation of 3-Methoxyquinoxalin-2-carboxamides as
Structurally Novel Serotonin Type-3 Receptor Antagonists
Radhakrishnan Mahesh, Thangaraj Devadoss, Arghya Kusum Dhar, Sudali Muthu Venkatesh,
Sourabh Mundra, Dilip Kumar Pandey, Shvetank Bhatt, and Ankur Kumar Jindal
Faculty Division-III (FD-III), Department of Pharmacy, Birla Institute of Technology & Science, Pilani,
Rajasthan, India
Employing a ligand-based approach, 3-methoxyquinoxalin-2-carboxamides were designed as
serotonin type-3 (5-HT3) receptor antagonists and synthesized from the starting material o-
phenylenediamine in a sequence of reactions. The structures of the synthesized compounds were
confirmed by spectral data. These carboxamides were investigated for their 5-HT3 receptor
antagonisms in longitudinal muscle myenteric plexus preparations from guinea-pig ileum against
a standard 5-HT3 agonist, 2-methy-5-HT, and their antagonism activities are expressed as pA2 values.
Compounds 6a (pA2: 7.2), 6e (pA2: 7.0), 6f (pA2: 7.5), 6g (pA2: 7.5), 6n (pA2: 7.0), and 6o (pA2: 7.2) exhibited
antagonism greater than that of the standard 5-HT3 antagonist, ondansetron (pA2: 6.9).
Keywords: 3-Methoxyquinoxalin-2-carboxamides / 5-HT3 receptor antagonists / Ligand-based drug design /
Quinoxalines / Serotonin
Received: January 30, 2012; Revised: April 4, 2012; Accepted: April 12, 2012
DOI 10.1002/ardp.201200038
Introduction
who are undergoing surgery or radiation therapy [5–8]. The
clinically existing 5-HT3 receptor antagonists substantially
increase the patient compliance for anti-cancer treatment [7]
by decreasing their side-effects (nausea and vomiting), but
unfortunately these antagonists are ineffective in 10–30% of
patients [9, 10]. Further they possess chiral center(s), which
increases the synthetic cost of these drugs [11]. This discussion
clearly stresses the requirements of new 5-HT3 receptor
antagonists. Based on the Hibert et al. [12] pharmacophore
model (Fig. 1), several new chemical entities have been reported
so far as 5-HT3 receptor antagonists [13–16].
Serotonin is a major neurotransmitter identified first from
serum and chemically known as 5-hydroxytryptamine (5-HT).
More than 90% of the body serotonin is located in the per-
ipheral system such as enterochromaffin cells, platelets, car-
diovascular system, and kidney, and to some extent is also
present in the central nervous system [1, 2]. It is implicated in
various physiological and patho-physiological conditions, by
acting through its receptor subtypes (5-HT1–7) [3]. Among
these receptor subtypes, 5-HT3 is unique, a ligand gated
ion channel receptor [4], whereas other receptor subtypes
belong to the superfamily of G-protein coupled receptors
(GPCR). Antagonists of this 5-HT3 receptor displayed anti-
emetic action in cancer chemo-/radiotherapy induced nausea
and vomiting. Nausea and vomiting are the most common
adverse effects of the existing chemotherapeutic agents and
these side-effects occur in a substantial number of patients
In our previous studies [13, 16] various 3-substituted
quinoxalin-2-carboxamides (consisting of Mannich base as
linking unit for piperazine moiety and quinoxaline nucleus,
Fig. 2) were assessed as 5-HT3 receptor antagonists; unfortu-
nately none of the compounds exhibited antagonism greater
than or equal to ondansetron, a standard 5-HT3 receptor
antagonist. Recently, we have demonstrated Mannich base
free quinoxalin-2-carboxamides as 5-HT3 receptor antagonists,
where piperazines are directly connected with quinoxaline via
amide carbonyl group, which yielded several potent antagonists
[17, 18]. So in the current study to discover new 5-HT3 receptor
antagonists without chiral center, current attempts were
focused on developing 3-methoxyquinoxlin-2-carboxamides
Correspondence: Thangaraj Devadoss, Research Scholar, Faculty
Division-III (FD-III), Department of Pharmacy, Birla Institute of Technology
& Science, Pilani, Rajasthan-333031, India.
E-mail: tdevadoss@gmail.com
Fax: þ9101596244183
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R. Mahesh et al.
Arch. Pharm. Chem. Life Sci. 2012, 000, 1–8
formations for each compound) of the designed molecules
were generated by ACDLABS-10.0/3D Viewer (CHARMM
parameterization) and the pharmacophoric distances were
measured from centroid of quinoxaline ring to oxygen of
the carbonyl group, carbonyl oxygen to basic nitrogen atom
(N4 of piperazines, heterocyclic nitrogen, and nitrogen of
tertiary amines), and centroid of quinoxaline residue to
basic nitrogen. The distances between the pharmacophoric
elements of the designed compounds complied with
the above-mentioned pharmacophoric model, except com-
pounds tryptamine and N,N-diethyl-p-phenylenediamine-
based carboxamide, which showed slight variation in the
distances between centroid of quinoxaline to basic nitrogen.
Results are summarized in Table 1 and represented in
Fig. 3. In order to attain the better pharmacokinetic (absorp-
tion, distribution, metabolism, and excretion) profile,
during the design of the new compounds Lipinski’s rules
were considered, i.e., hydrogen bond donor atoms not more
than 5, hydrogen bond acceptor atoms not more than 10,
log P-value not higher than 5 and molecular weight not
higher than 500 [19].
Figure 1. Pharmacophore model of 5-HT3 receptor antagonists.
CH2R1
O
N
N
H
OH
N
R
R2
R = Cl, OCH3, OC2H5
R1 = Piperazinyl, methylpiperazinyl,
ethylpiperazinyl
R2 = H, piperazinyl, methylpiperazinyl,
ethylpiperazinyl
Figure 2. Basic structure of Mannich base compounds.
Synthesis of 3-methoxyquinoxalin-2-carboxamides
The synthetic protocol of 3-methoxyquinoxalin-2-carbox-
amides is depicted in Scheme 1. The penultimate intermedi-
ate, i.e., 3-chloroquinoxalin-2-carboxylic acid (4) was
synthesized in multi-gram quantity from the starting
material, o-phenylenediamine, as per literature method (with
slight modification) [20]. The quinoxaline skeleton, ethyl 3-
oxo-3,4-dihydroquinoxalin-2-carboxylate (2) was constructed
from the starting material o-phenylenediamine by condens-
ing with diethyl ketomalonate, which on chlorination with
devoid of Mannich base, as potential 5-HT3 receptor
antagonists.
Results and discussion
Drug design
The 3-methoxyquinoxalin-2-carboxamides were designed
based on the Hibert et al. [12] pharmacophoric model.
The minimum energy conformation (three least energy con-
Table 1. Distances between the pharmacophoric elements of 6a–oa)
Compound
Centroid of
quinoxaline-carbonyl oxygen
Carbonyl
oxygen-basic nitrogen
Centroid of
quinoxaline-basic nitrogen
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
3.710 ꢀ 0.003
3.710 ꢀ 0.004
3.709 ꢀ 0.006
3.708 ꢀ 0.002
3.708 ꢀ 0.002
3.710 ꢀ 0.001
3.703 ꢀ 0.007
3.704 ꢀ 0.004
3.710 ꢀ 0.005
3.713 ꢀ 0.001
3.704 ꢀ 0.010
3.704 ꢀ 0.007
3.708 ꢀ 0.001
3.713 ꢀ 0.003
3.720 ꢀ 0.006
4.954 ꢀ 0.011
4.940 ꢀ 0.029
4.953 ꢀ 0.035
4.970 ꢀ 0.011
4.958 ꢀ 0.010
4.959 ꢀ 0.017
4.922 ꢀ 0.010
4.950 ꢀ 0.011
4.961 ꢀ 0.010
4.969 ꢀ 0.009
5.130 ꢀ 0.034
5.088 ꢀ 0.030
6.496 ꢀ 0.053
6.222 ꢀ 0.025
5.027 ꢀ 0.018
6.616 ꢀ 0.019
6.632 ꢀ 0.016
6.646 ꢀ 0.033
6.665 ꢀ 0.026
6.651 ꢀ 0.023
6.645 ꢀ 0.017
6.726 ꢀ 0.031
6.725 ꢀ 0.062
6.713 ꢀ 0.037
6.713 ꢀ 0.045
7.639 ꢀ 0.003
7.654 ꢀ 0.027
9.475 ꢀ 0.025
9.317 ꢀ 0.025
7.539 ꢀ 0.019
a)
Distances calculated for 3D optimized structures for at least three conformations of each compound, using CHARMM
˚
Parameterization (ACDLABS-10.0/3D Viewer) and the values are represented as mean ꢀ SD in A.
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Arch. Pharm. Chem. Life Sci. 2012, 000, 1–8
Structurally Novel 5-HT3 Receptor Antagonists
3
Amide Carbonyl
Oxygen
Amide Carbonyl
Oxygen
_
5.0 6.4 Å
3.7 Å
3.7 Å
4.9 Å
Centroid of
Quinoxaline
Distal Nitrogen
of Piperazine
Basic
Centroid of
Quinoxaline
_
Nitrogen
_
7.5 9.4 Å
Compounds 6k 6o
6.6 6.7 Å
_
_
Compounds 6a 6j
Figure 3. Distances between the pharmacophoric elements of 6a–o.
phosphorous oxychloride afforded the ethyl 3-chloroquinox-
alin-2-carboxylate (3) in quantitative yield. The obtained
chloro ester compound (3) upon alkaline hydrolysis followed
by acidification furnished the 3-chloroquinoxalin-2-carboxy-
lic acid (4) in good yield. This penultimate intermediate’s
chlorine atom was replaced by methoxy group under micro-
wave condition, which resulted in the formation of key
intermediate (5). The target 3-methoxyquinoxalin-2-carbox-
amides were synthesized by coupling the key intermediate,
3-methoxyquinoxalin-2-carboxylic acid with appropriate
amines in the presence of coupling agents EDC ꢁ HCl and
HOBt under inert atmosphere, nitrogen gas. In large scale,
synthesis of ethyl 3-oxo-3,4-dihydroquinoxalin-2-carboxylate
(2) was carried out in the presence of citric acid to improve
the yield [21].
Purity of the synthesized compounds was assessed by
running TLC with two different solvent systems using
three different detection (UV, I2, and ninhydrin) methods.
Homogeneity of one of the most active compounds (6f) was
confirmed by elemental data. In IR spectra, the piperazine-
based carboxamides showed strong absorption bands for
carbonyl groups at 1640 ꢀ 10 cmꢂ1, whereas the other
amine-based carboxamides showed an absorption band at
1680 ꢀ 15 cmꢂ1. Secondary carboxamides showed absorption
O
O
N
NH2
N
a
OC2H5
b
OC2H5
NH2
N
H
2
O
N
Cl
1
3
c, d
O
O
O
N
N
N
N
N
N
OH
f, g
OH
e
N
R
N
4
Cl
OCH3
O
OCH3
5
_
6a 6j
R = 6a:C6H5-
f, g
6b:o-MeO-C6H4-
6c:p-MeO-C6H4-
6d:p-Cl-C6H4-
6e:m-Cl-C6H4-
6f:m-CF3-C6H4-
6g:C6H5-CH2-
6h:CH3-
N
R
N
H
R = 6k:(Me)2N-CH2-CH2-
6l:(Et)2N-CH2-CH2-
6m:2-(Indol-3-yl)ethyl-
6n:p-N(Et)2-C6H4-
6o:3-Pyridyl-
N
OCH3
6i:CH3-CH2-
6j:CH2=CH-CH2-
_
6k 6o
Reagents and conditions: (a) Diethyl ketomalonate, ethanol, reflux, 6 h, 60%; (b) POCl3, DMF, reflux, 30 min 80%; (c)
Na2CO3, reflux, 6 h; (d) dil. HCl, 94%; (e) NaOCH3, methanol, MWI (420 Watt), 6 min, dil. HCl, 85%; (f) EDC·HCl, HOBt,
THF, N2, 0 °C–rt, 1 h; (g) amines, rt, 6 h.
Scheme 1. Synthetic route of 3-methoxyquinoxalin-2-carboxamides.
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R. Mahesh et al.
Arch. Pharm. Chem. Life Sci. 2012, 000, 1–8
at 3260 ꢀ 30 cmꢂ1 for N–H stretching and this absorption
band was absent in tertiary carboxamides. Compound 6m
showed two N–H stretching absorption bands, viz. one for
the amide N–H and the other for the indole N–H group. In
proton NMR spectra, the chemical shift values of the amide
N–H proton appeared between d 10.03 and 8.05. The aromatic
amine-based carboxamides, 6n and 6o, showed signals for the
amide N–H proton at d 10.03 and d 9.86, respectively. The
amides obtained from the aliphatic amines showed signal
for amide proton in the range of d 8.12–8.05, which (signal)
was absent in piperazine-based carboxamides. The piperazine-
based carboxamides displayed piperazine protons at ꢃd 4.00,
3.46, 3.35, and 3.10 as triplet with two protons in each signal,
when the distal nitrogen was attached to a phenyl residue. On
the other hand, when the distal nitrogen was attached to
aliphatic group containing compounds, the chemical shift
value of piperazine protons was observed as a triplet in the
region of ꢃd 3.80, 3.25, 2.45, and 2.30 (two protons in
each signal). The signals at ꢃd 2.45 and 2.30 corresponded
to piperazine protons vicinal to the distal nitrogen. The low
chemical shift values of these protons were due to the positive
inductive effect of the alkyl residue present on the distal
nitrogen. The splitting patterns of the piperazine protons were
greatly altered when the distal nitrogen was protonated, i.e.,
in hydrochloride salt form, e.g.: NMR spectra of compounds 6g
and 6i as hydrochloride salts showed piperazine protons in
the region between ꢃd 4.80 and 2.00. The salt proton of
the synthesized compounds showed a broad singlet signal
at ꢃd 13.00.
Pharmacology and preliminary SAR of
3-methoxyquinoxalin-2-carboxamides
All the synthesized molecules showed 5-HT3 receptor
antagonistic activity; the pharmacological data are presented
in Table 2. N-Phenylpiperazine was coupled with 3-methoxy-
quinoxalin-2-carboxylic acid to give product 6a which dis-
played stronger antagonism with a pA2 value of 7.2, greater
than the standard drug, ondansetron (pA2: 6.9). In order to get
more potent compounds several modifications were carried
out; initially a methoxy substituent was introduced on the
3-position of the phenyl ring of piperazine; the resultant
compound exhibited antagonism equal to ondansetron,
but lesser than 6a (pA2: 6.9). In contrast, the corresponding
regioisomer of 6b, i.e., amide 6c bearing methoxy substituent
at 4-position of phenyl ring of piperazine, markedly lost its
antagonistic potential (pA2: 5.3). Next, methoxy group was
replaced with an electron withdrawing substituent, a chlorine
atom, which lead to the formation of potent carboxamides 6d
Table 2. Physical constants and pharmacological data of 3-methoxyquinoxalin-2-carboxamides
O
O
N
N
R
N
N
N
N
H
OMe
N
R
OMe
Compound
R
% Yielda)
mp (8C)
log P-valueb)
Antagonism to
2-Me-5-HT (pA2)c)
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
C6H5–
80
82
84
82
86
76
84
78
78
74
69
72
92
85
89
–
160–162
136–140
130–132
186–188
96–98
96–100
198–200d)
84–86
208–210d)
semisolid
semisolid
semisolid
208–210
108–110
176–178
–
3.43
3.30
3.30
3.98
3.98
4.35
3.08
1.35
1.69
2.04
1.36
2.04
2.91
3.98
2.40
–
7.2
6.9
5.3
6.7
7.0
7.5
7.5
6.4
5.9
4.1
6.1
6.4
5.8
7.0
7.2
6.9
o-MeO–C6H4–
p-MeO–C6H4–
p-Cl–C6H4–
m-Cl–C6H4–
m-CF3–C6H4–
C6H5–CH2–
CH3–
CH3–CH2–
–
CH2 CH–CH –
–
2
(Me)2N–CH2–CH2–
(Et)2N–CH2–CH2–
2-(Indol-3-yl)ethyl–
p-N(Et)2–C6H4–
3-Pyridyl–
Ondansetron
–
a)
Yields refers to isolated pure product.
Log P-values were calculated using ChemBioDraw Ultra 11 (Cambridge Software).
pA2 values are the means of two separate experiments. SE was less than 10% of the mean.
Melting points were recorded as hydrochloride salt and are uncorrected.
b)
c)
d)
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Arch. Pharm. Chem. Life Sci. 2012, 000, 1–8
Structurally Novel 5-HT3 Receptor Antagonists
5
(pA2: 6.7). Changing the position of the chlorine atom from
4-position to 3-position was well tolerated and the resulting
compound 6e displayed good antagonism (pA2: 7.0).
Changing chlorine atom with trifluromethyl group, another
electron withdrawing substituent, increased the hydro-
phobicity and potency of the resultant compound 6f (pA2
value of 7.5). Incorporation of a methylene group between
the distal nitrogen and the phenyl group of piperazine
furnished another potent compound 6g (pA2: 7.5).
showed antagonism greater than the standard 5-HT3
antagonist, ondansetron (pA2: 6.9). So, extensive studies are
planned to be carried out further on these molecules to
furnish clinically useful 5-HT3 receptor antagonists, which
is the future extension of the present work.
Experimental
Chemistry
The minimum energy conformations of the designed molecules
were generated by ACDLABS-10.0/3D Viewer (CHARMM parame-
terization). All the chemicals and reagents were obtained from
Spectrochem Pvt. Ltd. (India), S. D. Fine Chem Limited (India), and
Aldrich (USA). Microwave irradiations were carried out in a
CATA-R microwave synthesizer. Reactions were monitored by
TLC, which was performed with 0.2 mm Merck pre-coated silica
gel 60 F254 aluminum sheets. Compounds were detected by UV,
iodine chamber, and by dipping the TLC plates in ethanolic
solution of ninhydrin and heating. Melting points (uncorrected)
were determined on a Buchi 530 melting point apparatus. IR
spectra (nmax in cmꢂ1) were recorded on a Jasco IR Report-100
infrared spectrophotometer or a Shimadzu IR Prestige-21 FT-IR
spectrophotometer, 1H NMR spectra were recorded at 400 MHz
on a Bruker Avance-II, FT NMR spectrometer using TMS as
internal standard (chemical shifts in d, ppm), elemental analysis
(C, H, N) on a CHNS-O analyzer (Flash EA 1112).
Next, modification was accomplished by replacing aryl
residue (phenyl) with aliphatic moiety (methyl) on the distal
nitrogen of piperazine, which resulted in amide 6h with
moderate antagonism (pA2: 6.4). Higher homologation, i.e.,
methylpiperazine into ethylpiperazine, afforded a mild
antagonist 6i with pA2 value of 5.9; further increment in
hydrophobicity by increasing the chain length led to the
formation of the least active compound 6j (pA2: 4.1). These
results indicated that the presence of a phenyl group is
necessary to display better 5-HT3 receptor antagonism than
the alkyl group alone on the piperazine moiety, with an
exception of compound 6c.
Finally, various primary amines, viz. N,N-dimethylethyl-
enediamine, N,N-diethylethylenediamine, tryptamine, N,N-
diethyl-p-phenylenediamine, and 3-aminopyridine, were
coupled with 3-methoxyquinoxalin-2-carboxylic acid to struc-
turally mimic the role of piperazine. The N,N-dimethylethyl-
enediamine-based carboxamide 6k showed moderate
antagonism (pA2: 6.1) and slight improvement in the
antagonistic profile was observed for its corresponding
higher homologue (6l, pA2: 6.4). The tryptamine and p-phenyl-
enediamine-based carboxamides, 6m and 6n, showed mod-
erate (pA2: 5.8) and strong antagonism (pA2: 7.0), respectively.
The carboxamide 6o formed as a result of coupling of
3-aminopyridine with 3-methoxyquinoxalin-2-carboxylic
acid showed antagonism (pA2: 7.2) greater than the reference
standard drug. The compounds (6k–o) with slight deviation
in the distances between carbonyl oxygen to basic nitrogen/
aromatic to basic nitrogen pharmacophore element showed
moderate to strong antagonism. These results indicated that
these compounds (6k–o) may interact with the receptor in an
allosteric site or the interacting sites of the receptor may have
the favorable flexibility (conformational changes) toward
carbonyl oxygen/basic nitrogen atom, when these molecules
approach the 5-HT3 receptors.
Synthesis of ethyl 3-oxo-3,4-dihydroquinoxalin-2-
carboxylate (2)
o-Phenylenediamine (20 g, 0.184 mol) was placed in a 1 L three-
neck round bottom flask equipped with a mechanical stirrer and
a thermocouple. Ethanol (200 mL) was added to the reactor, and
the mixture was stirred for 30 min. To the above reaction mass,
diethyl ketomalonate (33.90 g, 0.194 mol) was added in portions
over 30 min and the mixture was refluxed for 6 h. Solvent was
removed under vacuum; the obtained residue was recrystallized
from ethanol to afford the desired compound 2 in 60% yield. mp:
164–1678C; IR (KBr, cmꢂ1): 3440 (O–H lactim OH), 3040 (aromatic
–
–
C–H str.), 1750 (ester C O str.), 1660 (lactam C O str.), 1570, 1490
–
–
–
–
(C C, C N ring str.), 1465 (CH bend), 1375 (CH3 bend), 1300,
–
–
2
1100 (C–O str.); 1H NMR (400 MHz, CDCl3) d 12.95 (s, 1H, NH), 7.93
(m, 1H, quinoxaline), 7.61 (m, 1H, quinoxaline), 7.47 (m, 1H,
quinoxaline), 7.39 (m, 1H, quinoxaline), 4.54 (q, 2H, OCH2CH3),
1.46 (t, 3H, OCH2CH3).
Synthesis of ethyl 3-chloro-3,4-dihydroquinoxalin-2-
carboxylate (3)
Ethyl 3-oxo-3,4-dihydroquinoxalin-2-carboxylate (10 g, 0.045 mol)
was stirred with phosphorous oxychloride (32.20 g, 1.072 mol)
in a 1 L three-necked flask equipped with a mechanical stirrer,
reflux condenser, and a thermocouple, at ice bath temperature;
10 drops of dimethylformamide were added and the reaction
mass was refluxed for 30 min. Resultant mixture was diluted
with ethyl acetate and washed with aqueous sodium hydroxide
(2 ꢄ 100 mL), saturated sodium chloride solution (2 ꢄ 75 mL),
and dried over anhydrous sodium sulfate. The obtained product
was then evaporated under reduced pressure to afford the
desired compound 3 in 70–80% yield. mp: 34–368C; IR (KBr,
cmꢂ1): 3040 (aromatic C–H str.), 2950, 2890 (aliphatic C–H str.)
Conclusion
The results of the current study indicated that the chiral
center is not necessary for a compound to show strong 5-HT3
receptor antagonism, since several synthesized compounds,
6a (pA2: 7.2), 6e (pA2: 7.0), 6f (pA2: 7.5), 6g (pA2: 7.5), 6n pA2:
7.0), and 6o (pA2: 7.2) which are devoid of a chiral center,
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Arch. Pharm. Chem. Life Sci. 2012, 000, 1–8
–
–
–
–
1740 (ester C O str.) 1570, 1490 (C C, C N ring str.), 1465
(m, 1H, quinoxaline), 7.62–7.58 (m, 1H, quinoxaline), 7.30–7.26
(m, 2H, phenyl), 6.92 (q, 3H, phenyl), 4.13 (s, 3H, OCH3), 4.03 (t, 2H,
piperazine), 3.46 (t, 2H, piperazine), 3.33 (t, 2H, piperazine), 3.17
(t, 2H, piperazine).
–
–
(CH2 bending), 1375 (CH3 bending) 1300, 1100 (C–O str.);
1H NMR (400 MHz, CDCl3) d 8.09–8.07 (m, 1H, quinoxaline),
7.97–7.94 (m, 1H, quinoxaline), 7.81–7.72 (m, 2H, quinoxaline),
4.49 (q, 2H, OCH2CH3), 1.40 (t, 3H, OCH2CH3).
(4-(2-Methoxyphenyl)piperazin-1-yl)-
(3-methoxyquinoxalin-2-yl)methanone (6b)
Synthesis of 3-chloroquinoxalin-2-carboxylic acid (4)
Ethyl 3-chloro-3,4-dihydroquinoxalin-2-carboxylate (10 g, 0.042 mol)
was dissolved in aqueous methanol (80%, 285 mL). To this solution,
sodium carbonate (4.4 g, 0.042 mol) was added and the mixture was
refluxed for 6 h. Ethanol was removed under vacuum. The resultant
solution was acidified with 2 N HCl and the obtained solids were
filtered, washed with water, and dried in an oven overnight at 458C.
mp: 146–1508C; 1H NMR (CDCl3) d: 8.21 (dd, 1H, quinoxaline),
8.15 (dd, 1H, quinoxaline), 8.02–7.98 (m, 1H, quinoxaline), 7.95–
7.91 (m, 1H, quinoxaline); IR (KBr, cmꢂ1): 3460 (broad O–H
Yield: 82%; mp: 136–1408C; FT-IR (KBr, cmꢂ1): 3061, 2922, 2852,
2833 (C–H str.), 1643 (C O str.), 1151, 1091 (C–O str.); 1H NMR
–
–
(400 MHz, CDCl3) d 8.04 (d, 1H, quinoxaline), 7.88 (d, 1H, quinoxa-
line), 7.72 (t, 1H, quinoxaline), 7.60 (t, 1H, quinoxaline), 7.06
(quin, 1H, phenyl), 6.94 (d, 2H, phenyl), 6.89 (d, 1H, phenyl), 4.15
(s, 3H, OCH3), 4.07 (s, 2H, piperazine), 3.87 (s, 3H, OCH3), 3.49 (s,
2H, piperazine), 3.21 (s, 2H, piperazine), 3.06 (s, 2H, piperazine).
(4-(4-Methoxyphenyl)piperazin-1-yl)-
(3-methoxyquinoxalin-2-yl)methanone (6c)
–
–
–
str.COOH), 1745 (C O str.), 1590, 1490 (C C, C N ring str.), 1300,
–
1100 (C–O str.). Mass spectra of the compound showed molecular ion
–
–
Yield: 84%; mp: 130–1328C; FT-IR (KBr, cmꢂ1): 3043, 3004, 2956,
peak at m/z 207 (Mꢂ1)þ, 208 (M)þ, 209 (Mþ1)þ.
–
–
–
–
2906, 2833 (C–H str.), 1642 (C O str.), 1594, 1473 (C C, C N ring
–
–
1
str.), 1372 (CH2 bend), 1249, 1018 (C–O str.); H NMR (400 MHz,
CDCl3) d 7.96 (d, 1H, quinoxaline), 7.81 (d, 1H, quinoxaline), 7.65
(quin, 1H, quinoxaline), 7.53 (quin, 1H, quinoxaline), 6.85 (d, 2H,
phenyl), 6.78 (d, 2H, phenyl), 4.07 (s, 3H, OCH3), 3.98 (t, 2H,
piperazine), 3.70 (s, 3H, OCH3), 3.39 (t, 2H, piperazine), 3.14
(t, 2H, piperazine), 2.98 (t, 2H, piperazine).
Synthesis of 3-methoxyquinoxalin-2-carboxylic acid (5)
To a suspension of 3-chloroquinoxalin-2-carboxylic acid (5 g,
0.023 mol) in methanol, excess of sodium methoxide (2.8 g,
0.121 mol of sodium metal in methanol) was added and refluxed
for 6 min under microwave conditions (420 Watt). Methanol was
removed under vacuum; the resultant residue was diluted with
water and then acidified with 2 N HCl. The obtained solids were
filtered, washed, and dried to afford the product 5 in quantitative
yield. mp: 115–1198C; FT-IR (KBr, cmꢂ1): 3485 (broad O–H str.
COOH), 3143 (aromatic C–H str.), 2967, 2856 (aliphatic C–H str.),
(4-(4-Chlorophenyl)piperazin-1-yl)-
(3-methoxyquinoxalin-2-yl)methanone (6d)
Yield: 82%; mp: 186–1888C; FT-IR (KBr, cmꢂ1): 3046, 3000, 2956,
–
–
–
–
–
– –
2835 (C–H str.), 1639 (C O str.), 1573, 1496 (C C, C N ring str.),
– –
–
–
1730 (C O str.), 1570, 1450 (C C, C N ring str.), 1225, 1093 (C–O
–
1
1
str.); H NMR (400 MHz, DMSO-d6) d 9.69 (s, 1H, COOH), 8.05 (dd,
1H, quinoxaline), 7.91 (dd, 1H, quinoxaline), 7.86–7.82 (m, 1H,
quinoxaline), 7.73–7.69 (m, 1H, quinoxaline), 4.08 (s, 3H, OCH3).
Mass spectra of the compound showed molecular ion peak at
m/z 203 (Mꢂ1)þ, 204 (M)þ, 205 (Mþ1)þ.
1477, 1388 (CH3, CH2 bend), 1020 (C–O str.); H NMR (400 MHz,
CDCl3) d 8.03 (dd, 1H, quinoxaline), 7.88 (dd, 1H, quinoxaline),
7.73 (td, 1H, quinoxaline), 7.61 (quin, 1H, quinoxaline), 7.23
(d, 2H, phenyl), 6.85 (d, 2H, phenyl), 4.14 (s, 3H, OCH3), 4.03
(t, 2H, piperazine), 3.46 (t, 2H, piperazine), 3.30 (t, 2H, pipera-
zine), 3.14 (t, 2H, piperazine).
General procedure for the synthesis of
3-methoxyquinoxalin-2-carboxamides (6a–o)
4-(3-Chlorophenyl)piperazin-1-yl)-
(3-methoxyquinoxalin-2-yl)methanone (6e)
To 0.5 g (0.0024 mol) of 3-methoxyquinoxalin-2-carboxylic acid
taken in a 100 mL round bottom flask, 2 equivalents (0.92 g,
0.0047 mol) of EDC ꢁ HCl was added and stirred with 5 mL of
dry THF in an inert atmosphere (nitrogen) at 08C for 15 min.
To the above reaction mixture, 1-hydroxybenzotriazole (0.74 g,
0.0047 mol) was added and stirred for another 45 min. To the
above mixture, 1 equivalent of appropriate amines was added
and stirring continued for 6 h. The reaction mixture was con-
centrated under reduced pressure, the resultant mass was
diluted with dichloromethane or ethyl acetate, washed with
aqueous sodium bicarbonate (2 ꢄ 50 mL), saturated sodium
chloride solution (2 ꢄ 50 mL), and dried over anhydrous sodium
sulfate, which were then evaporated under reduced pressure to
afford the desired compounds.
Yield: 86%; mp: 96–988C; FT-IR (KBr, cmꢂ1): 3061, 2999, 2960,
–
–
–
2912, 2827 (C–H str.), 1643 (C O str.), 1595 (C C, C N ring str.),
–
–
–
1435, 1390 (CH3, CH2 bend); 1H NMR (400 MHz, CDCl3) d 7.95 (dd,
1H, quinoxaline), 7.81 (dd, 1H, quinoxaline), 7.65 (sep, 1H, qui-
noxaline), 7.53 (sep, 1H, quinoxaline), 7.11 (t, 1H, phenyl), 6.81–
6.78 (m, 2H, phenyl), 6.73–6.71 (m, 1H, phenyl), 4.06 (s, 3H, OCH3),
3.94 (t, 2H, piperazine), 3.38 (t, 2H, piperazine), 3.26 (t, 2H,
piperazine), 3.10 (t, 2H, piperazine).
(3-Methoxyquinoxalin-2-yl)(4-(3-(trifluoromethyl)-
phenyl)piperazin-1-yl)methanone (6f)
Yield: 76%; mp: 96–1008C; FT-IR (KBr, cmꢂ1): 3062, 3035, 2958,
–
–
–
–
–
2912, 2833 (C–H str.), 1643 (C O str.), 1610, 1477 (C C, C N ring
–
str.); 1H NMR (400 MHz, CDCl3) d 8.03 (dd, 1H, quinoxaline), 7.90
(dd, 1H, quinoxaline), 7.74 (td, 1H, quinoxaline), 7.61 (sep, 1H,
quinoxaline), 7.38 (t, 1H, phenyl), 7.13 (t, 2H, phenyl), 7.09 (t, 1H,
phenyl), 4.14 (s, 3H, OCH3), 4.05 (t, 2H, piperazine), 3.49 (t, 2H,
piperazine), 3.39 (t, 2H, piperazine), 3.23 (t, 2H, piperazine). Anal.
Calcd. for C21H19F3N4O2: C, 60.57; H, 4.60; N, 13.46; O, 7.68.
Found: C, 60.59; H, 4.59; N, 13.49.
(3-Methoxyquinoxalin-2-yl)(4-phenylpiperazin-1-yl)-
methanone (6a)
Yield: 80%; mp: 160–1628C; FT-IR (KBr, cmꢂ1): 3052, 3003, 2991,
–
–
–
–
2945, 2856 (C–H str.), 1643 (C O str.), 1598, 1485 (C C, C N
–
–
ring str.), 1149, 1053 (C–O str.); 1H NMR (400 MHz, CDCl3) d 8.03
(dd, 1H, quinoxaline), 7.88 (dd, 1H, quinoxaline), 7.74–7.70
ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Arch. Pharm. Chem. Life Sci. 2012, 000, 1–8
Structurally Novel 5-HT3 Receptor Antagonists
7
–
–
–
1565, 1500 (C C, C N ring str.), 1460, 1380 (CH , CH bend)
–
3
2
(4-Benzylpiperazin-1-yl)(3-methoxyquinoxalin-2-yl)-
methanone hydrochloride (6g)
1320, 1060 (C–O str.); 1H NMR (400 MHz, CDCl3) d 8.05 (s, 1H,
amide), 8.00 (dd, 1H, quinoxaline), 7.80 (dd, 1H, quinoxaline),
7.67 (sep, 1H, quinoxaline), 7.54 (sep,1H, quinoxaline), 4.13
(s, 3H, OCH3), 3.51 (q, NHCH2CH2N(CH2CH3)2), 2.64 (t, 2H,
NHCH2CH2N(CH2CH3)2), 2.54 (q, 4H, NHCH2CH2N(CH2CH3)2),
1.00 (t, 6H, NHCH2CH2N(CH2CH3)2).
Yield: 84%; mp: 198–2008C; FT-IR (KBr, cmꢂ1): 2981, 2701, 2601,
–
–
–
2551 (C–H str.), 1651 (C O str.), 1579, 1469 (C C, C N ring str.),
–
–
–
1336, 1284, 1222, 1157 (C–O str.); 1H NMR (400 MHz, CDCl3):
d 13.34 (s, 1H, salt proton), 7.87 (d, 1H, quinoxaline), 7.80 (d, 1H,
quinoxaline), 7.67 (t, 1H, aromatic), 7.55 (q, 3H, aromatic), 7.39
(s, 3H, aromatic), 4.80 (s, 1H, aliphatic), 4.19 (s, 3H, OCH3), 4.02
(s, 3H, aliphatic), 3.81 (d, 1H, aliphatic), 3.40 (t, 3H, aliphatic), 2.91
(s, 2H, aliphatic).
N-(2-(1H-Indol-3-yl)ethyl)-3-methoxyquinoxalin-2-
carboxamide (6m)
Yield: 92%; mp: 208–2108C; FT-IR (KBr, cmꢂ1): 3390 (sharp, N–H
–
str.), 3273 (sharp N–H str.), 3053, 2943, 2922 (C–H str.), 1666 (C O
str.), 1571 (C C, C N ring str.), 1440, 1390 (CH , CH bend), 1330,
–
(4-Methylpiperazin-1-yl)(3-methoxyquinoxalin2-yl)-
methanone (6h)
–
–
–
–
3
2
1226 (C–O str.); 1H NMR (400 MHz, CDCl3) d 8.11 (dd, 1H, amide),
7.90 (dd, 1H, quinoxaline), 7.86 (dd, 1H, quinoxaline), 7.80 (s, 1H,
NH), 7.75–7.70 (m, 2H, aromatic), 7.61–7.57 (m, 2H, aromatic),
7.40 (d, 1H, aromatic), 7.24–7.20 (m, 1H, aromatic), 7.15–7.11
(m, 2H, aromatic), 4.12 (s, 3H, OCH3), 3.88 (q, 2H, NHCH2CH2), 3.16
(t, 2H, NHCH2CH2).
Yield: 78%; mp: 84–868C; IR (CCl4, cmꢂ1): 3000, 2950, 2840 (C–H
–
–
–
str.), 1640 (C O str.), 1560 (C C, C N ring str.), 1450, 1360 (CH ,
–
–
–
3
CH2 bend), 1320, 1250, 1020 (C–O str.); 1H NMR (400 MHz, CDCl3):
d 7.94 (dd, 1H, quinoxaline), 7.79 (dd, 1H, quinoxaline), 7.63 (sep,
1H, quinoxaline), 7.51 (sep, 1H, quinoxaline), 4.05 (s, 3H, OCH3),
3.81 (t, 2H, piperazine), 3.24 (t, 2H, piperazine), 2.47 (t, 2H,
piperazine), 2.31 (t, 2H, piperazine).
N-(4-(Diethylamino)phenyl)-3-methoxyquinoxalin-2-
carboxamide hydrochloride (6n)
(4-Ethylpiperazin-1-yl)(3-methoxyquinoxalin-2-yl)-
methanone hydrochloride (6i)
Yield: 85%; mp: 108–1108C; FT-IR (KBr, cmꢂ1) (free base): 3251
–
(sharp N–H str.), 3062, 3000, 2924, 2854 (C–H str.), 1681 (C O
–
str.), 1542 (N–H bend), 1471, 1361 (CH3, CH2 bend), 1320, 1220
Yield: 78%; mp: 208–2108C; FT-IR (KBr, cmꢂ1): 3020, 3000,
–
1
(C–O str.); H NMR (400 MHz, CDCl3) d 13.74 (s, 1H, salt proton),
2956, 2922, 2661, 2503, 2348 (C–H str.), 1651 (C O str.), 1573,
–
–
–
1479 (C–C, C N ring str.), 1390 (CH bend), 1215, 1128, 1091 (C–O
2
10.03 (s, 1H, amide), 8.11 (d, 1H, aromatic), 8.04 (d, 2H, aromatic),
7.91 (d, 1H, aromatic), 7.80 (q, 4H, quinoxaline), 7.67 (t, 1H,
aromatic), 4.25 (s, 3H, OCH3), 3.72 (t, 2H, NCH2CH3), 3.36
(d, 2H, NCH2CH3), 1.26 (t, 6H, N(CH2CH3)2).
str.); 1H NMR (400 MHz, CDCl3) d 12.95 (s, 1H, salt proton),
7.89 (dd, 1H, quinoxaline), 7.82 (dd, 1H, quinoxaline), 7.68
(sep, 1H, quinoxaline), 7.54 (sep, 1H, quinoxaline), 4.84 (s, 1H,
piperazine), 4.06 (s, 3H, OCH3, 1H, piperazine), 3.77–3.27 (m, 4H,
piperazine), 3.11 (q, 2H, CH2CH3), 2.92 (s, 2H, piperazine), 1.44
(t, 3H, CH2CH3).
3-Methoxy-N-(pyridin-3-yl)quinoxalin-2-carboxamide (6o)
Yield: 89%; mp: 176–1788C; FT-IR (KBr, cmꢂ1): 3236 (sharp N–H
–
str.), 3097, 3057, 2951 (C–H str.), 1693 (C O str.), 1587, 1485,
–
–
(C C, C N ring str.); 1H NMR (400 MHz, CDCl3): d 9.86 (s, 1H,
(4-Allylpiperazin-1-yl)(3-methoxyquinoxalin-2-yl)-
methanone (6j)
–
–
–
amide), 8.83 (d, 1H, pyridine), 8.47 (dd, 1H, pyridine), 8.45 (dd, 1H,
pyridine), 8.08 (dd, 1H, quinoxaline), 7.90 (dd, 1H, quinoxaline),
7.79 (sep, 1H, quinoxaline), 7.65 (sep, 1H, quinoxaline), 7.35
(q, 1H, pyridine).
Semisolid, hygroscopic; yield: 74%; IR (CCl4, cmꢂ1): 3050, 3000,
–
–
–
–
2950, 2925, 2860 (C–H str.), 1650 (C O str.), 1580, 1470 (C C, C N
–
–
ring str.), 1360 (CH2 bend), 1220 (C–O str.); 1H NMR (400 MHz,
CDCl3) d 7.94 (dd, 1H, quinoxaline), 7.79 (dd, 1H, quinoxaline),
7.64 (sep, 1H, quinoxaline), 7.52 (sep, 1H, quinoxaline), 5.80–5.72
(m, 1H, olefinic), 5.12 (sep, 2H, olefinic), 4.06 (s, 3H, OCH3), 3.81 (t,
2H, piperazine), 3.24 (t, 2H, piperazine), 2.96 (d, 2H, methylene),
2.52 (t, 2H, piperazine), 2.36 (t, 2H, piperazine).
Pharmacology
All the animals were obtained from Hissar Agricultural
University, Hissar, Haryana, India, and were maintained in
colony cages at 23 ꢀ 28C, relative humidity of 45–55% under
a 12-h light/dark cycle, fed with standard animal feed, and water
ad libitum. The Institutional Animal Ethics Committee of the
Birla Institute of Technology & Science, Pilani, India, approved
the experimentation on animals (Protocol No. IAEC/RES/04/01/
Rev 01, dated 13.08.08). Compounds were assessed for their
serotonin type-3 receptor antagonism in male Dunkin Hartley
guinea-pigs (350–400 g).
N-(2-(Dimethylamino)ethyl)-3-methoxyquinoxalin-2-
carboxamide (6k)
Semisolid, hygroscopic; yield: 69%; IR (CCl4, cmꢂ1): 3241 (sharp
–
N–H str.), 2925, 2850 (C–H str.), 1640 (C O str.), 1460, 1320 (CH ,
–
3
CH2 bend), 1320, 1060 (C–O str.); 1H NMR (400 MHz, CDCl3) d 8.12
(s, 1H, amide), 8.08 (dd, 1H, quinoxaline), 7.87 (dd, 1H, quinoxa-
line), 7.76–7.72 (m, 1H, quinoxaline), 7.63–7.59 (m, 1H, quinoxa-
line), 4.20 (s, 3H, OCH3), 3.67 (q, 2H, NHCH2CH2NMe2), 2.72 (t, 2H,
NHCH2CH2NMe2), 2.41 (s, 6H, NHCH2CH2NMe2).
5-HT3 receptor antagonistic activity
For serotonin type-3 receptor antagonistic activity, guinea-pigs
were sacrificed by mild ether anesthesia followed by cervical
dislocation. The abdomen was cut open and a length of ileum
was excised about 2 cm from the ileo-caecal junction. The longi-
tudinal muscle myenteric plexus (LMMP), 3–4 cm in length, was
removed and mounted as per the method described elsewhere
[22]. The tissue was equilibrated for 30 min under a resting
N-(2-(Diethylamino)ethyl)-3-methoxyquinoxalin-2-
carboxamide (6l)
Semisolid, hygroscopic; yield: 72%; IR (CCl4, cmꢂ1): 3243 (sharp
–
N–H str.), 3050, 2950, 2925, 2850, 2800 (C–H str.), 1680 (C O str.),
–
ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

8
R. Mahesh et al.
Arch. Pharm. Chem. Life Sci. 2012, 000, 1–8
tension of 500 mg and constant aeration in a 40 mL organ bath
containing Tyrode solution maintained at 378C.
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Non-cumulative concentrations (10ꢂ8–10ꢂ4 M) of 2-methyl-5-
HT (Tocris, UK) were added with a 15 min dosing cycle (to prevent
desensitization) and left in contact with the tissue until the
maximal contraction had developed. A fixed 2-methyl-5-HT con-
centration (10ꢂ5 M), approximately ED80 was used for antagon-
ism studies. To study the antagonist effect of the test compounds
on the response evoked by 2-methyl-5-HT, the compounds were
added to the organ bath and left in contact with the tissue for at
least 10 min prior to the addition of 2-methyl-5-HT. The contrac-
tions were recorded using a T-305 force transducer coupled to a
Student’s physiograph (Bio Devices, Ambala, India). Antagonism
was expressed in the form of pA2 values (negative logarithm of
antagonist concentration producing a twofold shift of the ago-
nist concentration–activity curve), which were graphically deter-
mined [13, 16, 22, 23]. The pA2 values of the test compounds were
compared with that of the standard antagonist ondansetron
(Natco Pharma, Hyderabad, India).
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We are thankful to University Grants Commission (UGC), New Delhi,
India, for the financial support. We are also grateful to Birla Institute
of Technology and Science (BITS), Pilani, India for providing
infrastructural facilities and SAIF, Panjab University, Chandigarh,
India for providing analytical facilities.
[15] M. Ohta, T. Suzuki, T. Koide, A. Matsuhisa, T. Furuya,
K. Miyata, I. Yanagisawa, Chem. Pharm. Bull. 1996, 44, 991–
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[16] R. Venkatesha Perumal, R. Mahesh, Bioorg. Med. Chem. Lett.
2006, 16, 2769–2772.
The authors have declared no conflict of interest.
[17] R. Mahesh, T. Devadoss, D. K. Pandey, S. Bhatt, Bioorg. Med.
Chem. Lett. 2011, 21, 1253–1256.
[18] R. Mahesh, T. Devadoss, D. K. Pandey, S. K. Yadav, J. Enzyme
Inhib. Med. Chem. 2011, 26, 610–615.
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www.archpharm.com