Discovery of new anti-depressants from structurally novel 5-HT3 receptor antagonists: Design, synthesis and pharmacological evaluation of 3-ethoxyquinoxalin-2-carboxamides

Article abstract of DOI:10.1016/j.bmcl.2010.12.064

A novel series of 3-ethoxyquinoxalin-2-carboxamides were designed as per the pharmacophoric requirements of 5-HT₃ receptor antagonist using ligand-based approach. The desired carboxamides were synthesized from the key intermediate, 3-ethoxyquin

Full text of DOI:10.1016/j.bmcl.2010.12.064

Bioorganic & Medicinal Chemistry Letters 21 (2011) 1253–1256
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of new anti-depressants from structurally novel 5-HT3 receptor
antagonists: Design, synthesis and pharmacological evaluation
of 3-ethoxyquinoxalin-2-carboxamides
⇑
Radhakrishnan Mahesh, Thangaraj Devadoss , Dilip Kumar Pandey, Shvetank Bhatt
Pharmacy Group, FD-III, Birla Institute of Technology & Science, Pilani, Rajasthan 333 031, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A
novel series of 3-ethoxyquinoxalin-2-carboxamides were designed as per the pharmacophoric
Received 20 September 2010
Revised 13 December 2010
Accepted 15 December 2010
Available online 19 December 2010
requirements of 5-HT3 receptor antagonist using ligand-based approach. The desired carboxamides were
synthesized from the key intermediate, 3-ethoxyquinoxalin-2-carboxylic acid by coupling with appropri-
ate amines in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCÁHCl)
and 1-hydroxybenzotriazole (HOBt). The 5-HT3 receptor antagonism was evaluated in longitudinal
muscle myenteric plexus preparation from guinea pig ileum against 5-HT3 agonist, 2-methy-5-HT, which
was expressed in the form of pA2 values. Compound 6h (3-ethoxyquinoxalin-2-yl)(4-methylpiperazin-1-
yl)methanone was found to be the most active compound, which expressed a pA2 value of 7.7. In forced
swim test, the compounds with higher pA2 value exhibited good anti-depressant-like activity and
compounds with lower pA2 value failed to show activity as compared to the vehicle-treated group.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Quinoxalines
5-HT3 receptor antagonists
Anti-depressants
Forced swim test
Serotonin
Spontaneous locomotor activity
5-Hydroxytrptamine (5-HT, serotonin)
a
neurotransmitter
Previous research works in this area by our group12–14 and other
researchers3–6 have indicated the beneficial effects of 5-HT3 antag-
onists in depression and other central nervous system disorders.
Standard anti-depressants such as mirtazapine and mianserin have
been observed to possess serotonin type 3 receptor antagonism in
addition to 5-HT2A, 5-HT2C and a2 antagonism.15 The well known
5-HT3 receptor antagonists such as ondansetron, granisetron
(Fig. 1), etc. exhibit their anti-emetic action with negligible or few-
er side-effects. It was thought worthwhile to investigate 5-HT3
receptor antagonists that would have the beneficial role in the
treatment of depression. Though, the existing 5-HT3 receptor
antagonists have negligible side-effects, most of the compounds
possess chiral centre(s), which increases the synthetic cost of these
distributed in both peripheral and central nervous system,
involved in various physiological and patho-physiological condi-
tions, acting through the receptor subtypes (5-HT1–7).1 Among
these receptor subtypes, 5-HT3 is unique and is a ligand gated
ion channel receptor,2 whereas other receptor subtypes belong to
the super family of G-protein coupled receptor (GPCR). Antagonists
to this receptor, displayed anti-emetic action in cancer chemo-/
radio-therapy induced nausea and vomiting. In addition, they were
also found to exhibit anti-depressant, anxiolytic, anti-psychotic
and anti-inflammatory activities in pre-clinical studies.3–8 Antago-
nizing this ligand gated ion channel receptor for the beneficial of
depression would have added advantage as most of the classical
anti-depressants such as MAO inhibitors and tricyclic anti-depres-
sants are unfortunately well known for their drug–drug/–food
interaction and side-effects (anti-cholinergic, cardiovascular)
rather than their efficacy.9,10 The recent introduction of SSRI’s;
anti-depressants with lesser side-effects, improved the clinical
management of depression. However, these drugs also shared the
delayed onset of action like classical anti-depressants. Further all
the clinically useful agents possess withdrawal syndrome, except
agomelatine.11 This information emphasizes the demand of newer
anti-depressants with a safer and faster onset of action.
H3C
N
CH3
N
N
O
O
N
N
H3C
N
H
N
CH3
1
2
⇑
Corresponding author. Mobile: +91 9983525192; fax: +91 01596244183.
E-mail address: tdevadoss@gmail.com (T. Devadoss).
Figure 1. Chemical structures of (1) ondansetron (2) granisetron.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.12.064

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R. Mahesh et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1253–1256
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 were complied with the
abovementioned pharmacophore model. Compounds 6m and 6n
showed slight variation in the distances between centroid of quin-
oxaline to basic nitrogen (Supplementary data). To attain better
pharmacokinetic properties that is absorption, distribution, metab-
olism, and elimination the ‘‘Lipinski rules of five’’ was also adopted
for the designed molecules.21
Figure 2. Basic pharmcophore of 5-HT3 receptor antagonists.
drugs.16 Further, very few selective 5-HT3 antagonists are available
and hence the need of newer 5-HT3 antagonists are emphasized.
Several new chemical entities for 5-HT3 receptor antagonists have
been reported so far17,18 based on the Hibert et al. pharmacophore
model19 which consists of an aromatic ring, a linking carbonyl
group and a basic nitrogen centre at specific distances (Fig. 2). In
our previous study,20 various 3-substituted quinoxalin-2-carbox-
amides were evaluated (consists of Mannich base as linking unit
for piperazine moiety and quinoxaline nucleus) as 5-HT3 receptor
antagonists; unfortunately none of the synthesized compound ex-
ert their antagonism greater than or equal to standard 5-HT3
receptor antagonists, ondansetron. Keeping these aspects in mind,
the present study was aimed to develop newer 5-HT3 receptor
antagonists without chiral center. Attempts were focused on devel-
oping 3-ethoxyquinoxlin-2-carboxamides without Mannich base
as potential 5-HT3 receptor antagonists for the management of
depression.
Objective of the present study was to develop newer anti-
depressants from structurally novel 5-HT3 receptor antagonists.
Molecules were designed as 5-HT3 receptor antagonists based on
the Hibert et al. pharmacophore model, as mentioned above. The
minimum energy conformation (three least energy conformations
for each compound) of the designed molecules were generated
by ACDLABS-10.0/3D Viewer (CHARMM parameterization) and
the pharmacophoric distances measured from centroid of quinox-
aline ring to oxygen of the carbonyl group, carbonyl oxygen to
The synthetic protocols of the target compounds are illustrated
in the Scheme 1. The titled compounds were synthesized from the
starting material, o-phenylenediamine (1) in a sequence of reac-
tions. Initial condensation with diethyl ketomalonate followed by
chlorination using phosphorous oxychloride, afforded the chloro
ester compound (3) which on saponification followed by nucleo-
philic displacement with sodium ethoxide furnished the interme-
diate, 3-ethoxyquinoxalin-2-carboxylic acid (5). The carboxylic
acid group of the key intermediate (5) was amidated with appro-
priate amines (aryl/alkyl substituted piperazines and primary
amines) via active ester formation with the aid of EDCÁHCl and
HOBt to afford the desired product in good to excellent yields. IR
spectral analysis of the final compounds (6k–6o) showed
absorption bands at 3300 50 cmÀ1 due to N–H stretching, C@O
stretching vibrations of secondary (6k–6o) and tertiary carboxam-
ides (6a–6j) showed absorption bands at 1680 20 cmÀ1 and
1650 20 cmÀ1, respectively. The molecular ion of the final com-
pounds were observed as (M+1)+/(M+Na)+ in mass spectra.. Physi-
cal constants of the title compounds are represented in the Table 1.
All the animals were obtained from Hissar Agricultural Univer-
sity, Hissar, Haryana, India and maintained in colony cages at
23 2 °C, relative humidity of 45–55%, 12 h light/dark cycle and
fed with standard animal feed and water ad libitum. The Institu-
tional Animal Ethics Committee of the Birla Institute of Technology
and Science, Pilani, India, approved the experimentation on
animals (Protocol No. IAEC/RES/04/01/Rev 01, dated 13.08.08).
O
O
N
N
NH2
NH2
b
a
O
CH3
O
CH3
N
3
Cl
N
H
2
O
1
c
O
O
O
N
N
N
N
R
e, g
OH
d
OH
NH
OC2H5
N
5
OC2H5
N
4
Cl
6k_6o
e, f
O
N
N
N
N
OC2H5
R
6a_6j
Scheme 1. Synthetic route of 3-ethoxyquinoxalin-2-carboxamides. Reagents and conditions: (a) Diethyl ketomalonate, ethanol, reflux, 6 h, 60%; (b) POCl3, DMF, reflux,
30 min 80%; (c) 10% aq NaOH, rt, 1 h, dil HCl, 90% or Na2CO3, reflux, 6 h, dil HCl, 94%; (d) NaOCH2CH3, ethanol, MW, 6 min, dil HCl, 85%; (e) EDCÁHCl, HOBt, THF, N2, 0 °C–rt, 1 h;
(f) piperazines, 6 h; (g) R-NH2, 6 h.

R. Mahesh et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1253–1256
1255
Table 1
Physical constants of 3-ethoxyquinoxalin-2-carboxamides
Compd
R
% Yielda
Mp in °C
Molecular formulac
Log Pd
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
C6H5-
80
76
73
69
85
88
75
77
69
64
72
68
78
89
66
100–102
102–104
94–96
140–142
74–76
128–130
238–240b
Semi solid
Semi solid
Semi solid
Semi solid
Semi solid
114–116
96–100
C21H22N4O2
C22H24N4O3
C22H24N4O3
C21H21ClN4O2
C21H21ClN4O2
C22H21F3N4O2
C22H24N4O2
C16H20N4O2
C17H22N4O2
C18H22N4O2
C15H20N4O2
C17H24N4O2
3.76
3.64
3.64
4.32
4.32
4.69
3.42
1.69
2.03
2.38
1.70
2.37
3.25
4.32
2.02
o-MeO-C6H4-
p-MeO-C6H4-
p-Cl-C6H4-
m-Cl-C6H4-
m-CF3-C6H4-
C6H5-CH2-
CH3-
CH3-CH2-
CH2=CH-CH2-
(Me)2N-CH2-CH2-
(Et)2N-CH2-CH2-
2-(Indol-3yl)ethyl-
p-N(Et)2-C6H4-
3-Pridyl-
C
21H20N4O2
C21H24N4O2
16H14N4O2
116–118
C
a
b
c
Yields are refers to isolated pure compound.
Melting point was recorded in hydrochloride salt form.
Elemental (C, H, and N) analysis indicated that the calculated and observed values were within the acceptable limits ( 0.4%).
d
Log P values are calculated by using CHEMBIODRAW Ultra 11 (Cambridge Software).
Compounds were assessed for their serotonin type-3 receptor
antagonism in male Dunkin Hartley guinea pigs (350–400 g) and
for spontaneous locomotor activity (SLA) and anti-depressants
potentials in Swiss Albino mice (23 2 g), respectively.
of electron releasing group with chlorine atom on the phenyl ring,
increased the lipophilicity of the carboxamide 6d, but reduced the
potency (pA2: 6.0) of the compound 6d. On the other hand its
regioisomer, compound 6e25 that is chloro substituent on the 3rd
position of the phenyl ring displayed antagonism (pA2: 6.6) closer
to ondansetron. Increasing the electron withdrawing nature by
introducing CF3 group in place of chlorine atom, enhanced the
lipophilicity of the formed carboxamide 6f but markedly reduced
its potency (pA2: 5.1) as compared to the compound 6e. Incorpora-
tion of methylene group between distal nitrogen of piperazine and
phenyl group further weakened the antagonism, where the pA2
value of the obtained compound 6g was 4.6.
Next, aromatic radical on the distal nitrogen of the piperazine
was replaced with aliphatic group (phenyl group replaced with
methyl group) and the resultant carboxamide 6h26 showed prom-
inent antagonism (pA2: 7.7). Higher homologation of aliphatic rad-
ical on the distal nitrogen (methylpiperazine into ethylpiperazine)
resulted in increased lipophilicity but no enhancement in the
antagonism (pA2: 7.5). Further, increasing the length of alkyl chain
The target new chemical entities were evaluated for their 5-HT3
receptor antagonisms in longitudinal muscle myenteric plexus
preparation from guinea pig ileum against 5-HT3 agonist,
2-methy-5-HT. Antagonism was expressed as pA2 values, which
was determined according to the literature methods20,22–24 and
the results are summarized in the Table 2. Phenylpiperazine was
coupled with 3-ethoxyquinoxalin-2-carboxylic acid, the formed
carboxamide 6a, showed mild antagonism (pA2: 5.0). In order to
obtain potent antagonists, various substituents were introduced in
the aromatic moiety (phenyl ring) of the piperazine. First, a methoxy
group, an electron releasing substituent was introduced at 2nd po-
sition of phenyl ring resulting in improved antagonism, (pA2: 7.0),
which was greater than the standard drug, ondansetron (pA2: 6.9).
Potency of the carboxamide was slightly reduced while introducing
methoxy substituent at 4th position of the phenyl ring. Replacement
Table 2
Pharmacological data of 3-ethoxyquinoxalin-2-carboxamides
Compd
Antagonism to 2-Me-5-HT (pA2)a
Duration of immobility in seconds (FST)b
Locomotor scoresb (10 min)
Dose (mg/kg)
Dose (mg/kg)
1.0
0.5
2.0
1.0
0.5
2.0
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
5.0
7.0
6.8
6.0
6.6
5.1
4.6
7.7
7.5
6.8
6.9
4.7
7.2
5.0
4.8
6.9
—
134.0 26.0*
113.3 08.8*
114.6 22.4*
146.6 20.4
110.6 20.0*
148.0 07.6
160.0 23.0
94.0 18.0*
98.0 20.0*
127.0 13.0*
117.7 07.6*
162.0 21.0
104.0 14.0*
145.0 21.0
144.0 18.0
100.4 10.0*
—
—
382.3 29.0
360.0 43.4
356.4 56.5
364.1 24.5
351.5 39.3
356.5 22.4
366.2 26.4
349.6 41.2
360.4 28.9
360.1 44.3
349.3 47.8
362.2 33.0
350.4 45.4
374.0 29.0
365.0 23.0
388.1 10.3
—
—
115.3 2.6*
159.0 13.8
—
122.0 02.5*
121.6 06.4*
—
351.0 32.5
352.3 56.8
—
361.3 45.5
—
366.3 46.8
361.0 46.6
—
358.0 31.4
—
83.6 03.7*
—
—
76.6 12.9*
—
—
—
—
125.0 10.9*
159.3 07.8
152.0 05.8
133.6 12.1
—
130.0 09.1*
128.0 01.5*
118.0 08.7*
96.0 03.0*
—
353.0 51.5
349.3 36.3
345.3 39.7
345.0 31.7
—
356.3 35.0
351.6 46.4
351.6 39.2
342.6 33.0
—
150.3 14.3
—
79.3 21.8*
—
366.3 34.0
—
355.3 46.9
—
—
—
—
—
Ondansetron
Control
130.2 18.2*
165.6 03.2
95.1 06.5*
368.0 12.0
365.5 49.4
400.0 22.0
a
pA2 values are the means of two separate experiments. SE was less than 10% of the mean.
10% of PEG-400 in water was used as a vehicle, the values are expressed as mean, n = 8 per group. Data were analyzed by GRAPH PAD PRISM (3) software through one way
b
ANOVA followed by post hoc Dunnett’s test.
*
p <0.05 compared with vehicle-treated group (control).

1256
R. Mahesh et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1253–1256
on the distal nitrogen residue; introducing allyl group in place of
ethyl group, yielded the carboxamide 6j, whose antagonism (pA2:
6.8) was nearly equal to ondansetron but less than that of
compound 6h. In final modification, to serve the role of piperazine
(as basic nitrogen centre), various primary amines viz. N,N-dimeth-
ylethylenediamine, N,N-diethylethylenediamine, tryptamine, N,N-
diethyl-p-phenylenediamine and 3-aminopyridine were coupled
with 3-ethoxyquinoxalin-2-carboxylic acid. The obtained carbox-
amides (6k–6o) exhibited antagonism towards serotonin type-3
receptor, and among them 6m27 displayed antagonism (pA2: 7.2)
greater than the standard drug, followed by compound 6k, which
showed antagonism (pA2: 6.9) equal to ondansetron.
compounds are planned to obtain clinically useful anti-depressant
agents.
Acknowledgments
We are thankful to University Grants Commission (UGC), New
Delhi, India, for the financial support. We are grateful to Birla
Institute of Technology & Science (BITS), Pilani, India for providing
infrastructural facilities and SAIF, Panjab University, Chandigarh,
India for providing analytical facilities.
Supplementary data
Regardless of the 5-HT3 receptor antagonistic potency, all the
carboxamides were subjected to forced swim test (FST) in mice
model,13,28 to evaluate their anti-depressants activity. In the
preliminary anti-depressant screening, test compounds were
administered intra-peritonealy at a dose of 1 mg/kg body weight.
Among the test compounds, 6h and 6i significantly reduced the
duration of immobility in mice as compared to vehicle-treated
group, followed by compound 6m, 6e, 6b, 6k and 6j. The anti-
depressant-like effect of compound 6h and 6i are greater than
the positive control, ondansetron. Compounds with low pA2 values
failed to show anti-depressant-like effect on FST mice model. The
drug-induced stimulation/sedation sometimes leads to false-
positive/-negative results respectively in mice FST. In order to
eliminate the same, all the screened molecules are subjected to
SLA in actophotometer.13 Interestingly, none of the tested com-
pounds influenced the baseline locomotion of mice when observed
in actophotometer, Table 2.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.12.064.
References and notes
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Int. Clin. Psychopharm. 2004, 19, 271.
Based on the preliminary anti-depressant study a dose response
assay was performed for the selected (active) compounds in mice
FST and the results are summarized in Table 2. Compound 6b, 6e
and 6h significantly reduced the duration of immobility of mice
in all the tested doses. Whereas, compounds 6c, 6m, 6j, 6k and
6i were active only at 1 and 2 mg/kg body weight and failed to
show activity at lower dose (0.5 mg/kg body weight). The
anti-depressant-like effect of compounds 6h, 6b and 6m were
greater than the standard drug, ondansetron at the dose of 0.5
and 2 mg/kg body weight, respectively. Compounds 6j, 6k and
6m exhibited their anti-depressant-like effects in a dose-dependent
manner; on the other hand 6e displayed its activity in a biphasic
way. The dose-dependent and biphasic-effects exerted by the
synthesized compounds are in agreement with earlier reports on
the effects of 5-HT3 receptor antagonists in animal models of
depression.3,14 In this study, compounds with higher pA2 values sig-
nificantly reduced the duration of immobility of mice in FST, which
indicates the beneficial effects of 5-HT3 receptor antagonists in
depression. However, to map the exact mechanism of these novel
compounds, molecular and interaction studies are necessary, which
is expected to be carried out separately as an extension of the pres-
ent study.
12. Devadoss, T.; Pandey, D. K.; Mahesh, R.; Yadav, S. Pharmacol. Rep. 2010, 62, 245.
13. Mahesh, R.; Rajkumar, R.; Minasri, B.; Venkatesha Perumal, R. Pharmazie 2007,
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H. F. J. Med. Chem. 1993, 36, 2645.
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Yanagisawa, I. Chem. Pharm. Bull. 1996, 44, 991.
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25. (4-(3-Chlorophenyl)piperazin-1-yl)(3-ethoxyquinoxalin-2-yl)methanone (6e): 1H
NMR (CDCl3) d ppm: 8.03 (d, 1H, quinoxaline), 7.86 (d, 1H, quinoxaline), 7.73
(m, 1H, quinoxaline), 7.62 (m, 1H, quinoxaline), 7.21 (t, 1H, phenyl), 6.88 (d,
2H, phenyl), 6.81 (t, 1H, phenyl) 4.64 (q, 2H, OCH2), 4.03 (t, 2H, piperazine),
3.45 (t, 2H, piperazine), 3.35 (t, 2H, piperazine), 3.19 (t, 2H, piperazine), 1.48 (t,
3H, CH3); Mass spectra (ESI) of the compound exhibited the molecular ion peak
at m/z 396 (M)+, 398 (M+2)+; FT-IR (KBr, cmÀ1): 3061, 2981, 2918, 2829, 1633,
1593, 1573, 1479, 1417, 1325, 1236, 1151, 1012, 941, 912, 754, 688.
26. (3-Ethoxyquinoxalin-2-yl)(4-methylpiperazin-1-yl)methanone (6h): 1H NMR
In summary, a series of structurally novel 3-ethoxyquinoxalin-
2-carboxamides were designed as 5-HT3 receptor antagonists,
using ligand-based approach and the target molecules were syn-
thesized from the starting material o-phenylenediamine involving
a sequence of reactions. All the synthesized compounds exhibited
5-HT3 receptor antagonism, whereas compounds 6h, 6i, 6m and
6b showed antagonism greater than the standard drug, ondanse-
tron. Compounds with higher pA2 values significantly decreased
the duration of immobility of mice in FST as compared to control
group, reflecting their anti-depressant-like effect. The compounds
with lower pA2 values, failed to show activity as compared to the
vehicle-treated group and these results correlated the beneficial
effect of 5-HT3 antagonists in depression. Further studies on these
(CDCl3+DMSO-d6)
d ppm: 8.11 (dd, 1H, quinoxaline), 7.86 (dd, 1H,
quinoxaline), 7.74 (m, 1H, quinoxaline), 7.63 (m, 1H, quinoxaline), 4.60 (q,
2H, OCH2), 3.96 (t, 2H, piperazine), 3.48 (t, 2H, piperazine), 2.70 (t, 2H,
piperazine), 2.58 (t, 2H, piperazine), 2.40 (s, 3H, NCH3), 1.48 (t, 3H, CH3); Mass
spectra (ESI) of the compound exhibited the molecular ion peak at m/z 301
(M+1)+; FT-IR (KBr, cmÀ1): 3080, 2966, 2939, 2902, 1651, 1579, 1415, 1319,
1294, 1267, 1217, 1028, 1155, 763, 609.
27. N-(2-(1H-indol-3-yl)ethyl)-3-ethoxyquinoxaline-2-carboxamide (6m): 1H NMR
(CDCl3) d ppm: 8.22 (br s, 1H, CONH), 8.00 (dd, 1H, quinoxaline) 7.82 (dd, 2H,
quinoxaline), 7.73 (m, 2H, 1H, quinoxaline, 1H, indole), 7.58 (d, 1H, NH indole),
7.39 (d, 1H, indole), 7.22 (m, 1H, indole), 7.13 (m, 2H, indole), 4.60 (q, 2H,
OCH2CH3), 3.90 (q, 2H, NCH2), 3.16 (t, 2H, NCH2CH2), 1.42 (t, 3H, OCH2CH3);
Mass spectra (ESI) of the compound exhibited the molecular ion peak at m/z
361 (M+1)+; FT-IR (KBr, cmÀ1): 3278, 3184, 3041, 2989, 2951, 2914, 1666,
1588, 1514, 1462, 1369, 1222, 1136, 752, 773, 642.
28. Porsolt, R. D.; Bertin, A.; Jalfre, M. Arch. Int. Pharmacodyn. Ther. 1977, 229, 327.