Design, synthesis and structure-activity relationship of novel quinoxalin-2-carboxamides as 5-HT3 receptor antagonists for the management of depression

Article abstract of DOI:10.1016/j.bmcl.2010.08.128

A novel series of quinoxalin-2-carboxamides were designed based on the ligand-based approach, employing a three-point pharmacophore model; it consists of an aromatic residue and a linking carbonyl group and a basic nitrogen. The target new chemical entities were synthesized from the key intermediate, quinoxalin-2-carboxylic acid, by coupling it with various amines in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl) and 1-hydroxybenzotriazole (HOBt). The obtained compounds' structures were confirmed by spectral data. 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-methyl-5-HT, which was expressed in the form of pA₂ value. All the synthesized compounds showed antagonism towards 5-HT₃ receptor; based on this result, a structure-activity relationship was derived, which reveals that the aromatic residue in 5-HT₃ receptor antagonists may have hydrophobic interaction with 5-HT₃ receptor. Regardless of their antagonistic potentials, all the synthesized molecules were screened for their anti-depressant potentials by using forced swim test in mice model; interestingly none of the tested compounds affect the locomotion of mice in the tested dose levels. Compounds with significant pA₂ values exhibited good anti-depressant-like activity as compared to the vehicle-treated group.

Full text of DOI:10.1016/j.bmcl.2010.08.128

Bioorganic & Medicinal Chemistry Letters 20 (2010) 6773–6776
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis and structure–activity relationship of novel
quinoxalin-2-carboxamides as 5-HT3 receptor antagonists for the management
of depression
Radhakrishnan Mahesh a, Thangaraj Devadoss a, , Dilip Kumar Pandey a, Shvetank Bhatt a,
⇑
Shushil Kumar Yadav b
a Pharmacy Group, FD-III, Birla Institute of Technology and Science, Pilani 333 031, Rajasthan, India
b Central Animal Facility, FD-III, Birla Institute of Technology and Science, Pilani 333 031, Rajasthan, 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 quinoxalin-2-carboxamides were designed based on the ligand-based approach,
employing a three-point pharmacophore model; it consists of an aromatic residue and a linking carbonyl
group and a basic nitrogen. The target new chemical entities were synthesized from the key intermediate,
quinoxalin-2-carboxylic acid, by coupling it with various amines in the presence of 1-(3-dimethylamino-
propyl)-3-ethylcarbodiimide hydrochloride (EDCÁHCl) and 1-hydroxybenzotriazole (HOBt). The obtained
compounds’ structures were confirmed by spectral data. 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-methyl-5-HT, which was expressed in the form of pA2 value. All the
synthesized compounds showed antagonism towards 5-HT3 receptor; based on this result, a structure–
activity relationship was derived, which reveals that the aromatic residue in 5-HT3 receptor antagonists
may have hydrophobic interaction with 5-HT3 receptor. Regardless of their antagonistic potentials, all the
synthesized molecules were screened for their anti-depressant potentials by using forced swim test in
mice model; interestingly none of the tested compounds affect the locomotion of mice in the tested dose
levels. Compounds with significant pA2 values exhibited good anti-depressant-like activity as compared
to the vehicle-treated group.
Received 28 May 2010
Revised 5 August 2010
Accepted 27 August 2010
Available online 28 September 2010
Keywords:
Quinoxaline
Serotonin
Anti-depressants
Quinoxalin-2-carboxamides
5-HT3 receptor antagonists
Ó 2010 Elsevier Ltd. All rights reserved.
Depression affects 1 in 10 women and 1 in 50 men at some
stages in their life; in half of these cases, depression recurs and
about 15% of depressives commit suicide.1 The combined effect
of increased suicide risk and increased physical illness of this dis-
order shortens the life by one decade.2 Poor patient compliance
is the major reason for the recurrence of this disorder; this is often
due to the toxicities associated with the existing anti-depressant
drugs.3 The classical anti-depressants, monoamineoxidase inhibi-
tors, such as iproniazid and phenelzine, are well known for drug–
drug/food interaction than their therapeutic efficacy, since they
precipitate life-threatening hypertensive crises with tyramine-
containing foods.4 On the other hand typical TCAs such as mono-
amine reuptake inhibitors, amitriptyline and imipramine, were
associated with anticholinergic and cardiovascular side effects
and fatal condition in over dosage.4,5 Moreover their therapeutic
effects appear after 2–6 weeks of treatment, and the currently
available atypical anti-depressants are devoid of anticholinergic
and cardiovascular side effects. However these molecules are also
sharing the delayed onset of action like the classical mood eleva-
tors.6 Further, all the clinically existing anti-depressants except
agomelatine possess the discontinuation syndrome.7 This informa-
tion stresses the requirement of newer anti-depressants with a
safe and faster onset of action.
Drugs, which are antagonizing 5-HT3 receptor such as ondanse-
tron and granisetron predominantly express antiemetic action in
humans with lesser or negligible side effects. The various pre-clini-
cal studies8–11 including our previous work12,13 indicate the benefi-
cial effect of 5-HT3 receptor antagonist in depression and other CNS
disorders. The standard anti-depressants such as mirtazapine and
mianserin possess serotonin type 3 receptor antagonism,3 which
indicates that the 5-HT3 receptor antagonist would have a potential
role in the treatment of depression. The existing 5-HT3 receptor
antagonists share three common elements as pharmacophore,
which consists of an aromatic group, a linking carbonyl group and
a basic nitrogen centre. Based on the aforementioned, three-compo-
nent pharmacophore model, several research groups including our
group have designed and synthesized the new chemical entities as
5-HT3 receptor antagonists and they also explored the role of
carbonyl group and basic nitrogen atom in 5-HT3 receptor
⇑
Corresponding author. Mobile: +91 9983525192; fax: +91 01596244183.
E-mail address: tdevadoss@gmail.com (T. Devadoss).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.08.128

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R. Mahesh et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6773–6776
antagonists.14–21 But the role of aromatic group in 5-HT3 receptor
antagonists was not well explored regarding the intermolecular
interaction with 5-HT3 receptor. In addition most of the existing
5-HT3 receptor antagonists (ondansetron, azasetron, etc.) are hav-
ing chiral centre(s), which increases the synthetic cost of these
drugs. The existing 5-HT3 receptor antagonists’ structures are
shown in Figure 1.
OH
OH
N
NH2
NH2
a
OH
OH
N
2
1
b
Keeping these aspects in mind, the present work is an extent of
interest to develop newer anti-depressants and to find out the pos-
sible role of aromatic group in 5-HT3 receptor antagonists for the
interaction with 5-HT3 receptor, in addition to the development
of novel 5-HT3 receptor antagonists without chiral centre.
The aim was to produce newer anti-depressants that act as
5-HT3 receptor antagonist. Most of the existing 5-HT3 receptor
antagonists have three necessary pharmacophore elements as
mentioned above. Using this ‘Three Component Pharmacophore
model’ molecules were designed, in which nitrogen present in
the quinoxaline nucleus acts as basic centre, benzene ring as aro-
matic unit and amide group as carbonyl linker. Further, for the bet-
ter pharmacokinetic (absorption, distribution, metabolism and
excretion) profile all the molecules were designed according to
Lipinski Rules of Five.
The title target compounds were synthesized from the key
intermediate quinoxalin-2-carboxylic acid, by coupling with
various amines in the presence of 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (EDCÁHCl) and 1-hydroxybenzo-
triazole (HOBt) under nitrogen atmosphere. The key intermediate
was synthesized from the starting material o-phenylenediamine
as per the literature method (Scheme 1).22 All the synthesized
compounds were characterized by spectral data. IR spectral analy-
sis of the final compounds showed absorption bands at 3300
50 cmÀ1, 1640 50 cmÀ1 and 1540 20 cmÀ1 due to N–H, C@O
stretching and N–H bending; these N–H absorption bands were
absent in pyrrolidine-based carboxamide. In 1H NMR amide proton
signal appeared at d ꢀ9.80, quinoxaline protons appeared at d
ꢀ9.70, ꢀ8.20 and ꢀ7.90; for the compounds 4a–4l and for the ali-
phatic carboxamides, quinoxaline protons appeared at d ꢀ9.50,
ꢀ8.20, ꢀ8.10 and ꢀ7.90. Mass spectra (ESI) of most of the com-
pounds exhibited molecular ion as (M+1)+/(M+Na)+. Physical
constants of the title compounds are represented in 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-
O
N
OH
N
3
c,e
c,d
O
O
N
N
N
NH
R
N
5
N
4a-p
Scheme 1. Reagents and conditions: (a) D-fructose, 10% aq AcOH, 80 °C, 18 h, 45%;
(b) NaOH, 30% H2O2 , 60 °C, 3 h then 90 °C, 2 h, HCl, 50%; (c) EDCÁHCl, HOBt, THF, N2,
0 °C–rt, 1 h; (d) R-NH2, rt, 5 h; (e) pyrrolidine, rt, 5 h.
tional 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) and for spontaneous
locomotor activity and anti-depressants potentials in Swiss albino
mice (23 2 G), respectively.
Guinea pig ileum being rich in serotonin type 3 receptors was
used to evaluate the compounds synthesized for their 5-HT3 recep-
tor antagonism (in isolated guinea pig ileum) using 2-methyl-
5-hydroxytryptamine as serotonin type 3 agonist. Antagonism
was expressed in the form of pA2 values, which was determined
according to the literature methods.20,21,23,24 All the synthesized
compounds exhibited the antagonism towards 5-HT3 receptor;
pharmacological data of the title compounds are represented in
Table 2. Compounds 4i, 4n showed antagonism greater than the
standard 5-HT3 receptor antagonist, ondansetron; pA2 6.9 and
compounds 4a and 4m exhibited antagonism closer to that of the
standard drug. First aniline-based carboxamide was synthesized
by coupling quinoxalin-2-carboxylic acid with aniline and the
formed compound 4a25 exhibited good antagonism with a pA2 va-
lue of 6.8. In order to find out the possible role of aromatic (ben-
zene) group in 5-HT3 receptor antagonist, an electron-releasing
group was introduced first; methyl group on the benzene ring de-
creased the antagonism. Replacing methyl group with methoxy
group, which has stronger electron-releasing nature but lesser
lipophilic than methyl group, gave the less active compound 4c.
Incorporation of methylene and NH group between amino and
phenyl group of aniline decreased the potency of the correspond-
ing quinoxalin-2-carboxamides, 4d and 4e, whose pA2 values were
5.7 and 5.8, respectively. Hence it was decided to change the nat-
ure of substituent on the benzene ring; that is, replacing the elec-
tron-releasing group with the acetyl group, which is an electron-
withdrawing group, retained the antagonism for 5-HT3 receptor
and the pA2 value was greater than compounds with electron-
releasing groups but lesser than compound with no substituent
on the benzene ring. Based on this result, the strength of the elec-
tron-withdrawing nature was increased; introducing substituents
such as chlorine and nitro group in place of acetyl group, the resul-
tant carboxamides 4g, pA2 5.8 and 4h, pA2 5.0 were observed to
H3C
N
N
O
O
NH
N
O
N
N
O
2
CH3
1
CH3
N
O
N
Cl
O
NH
Cl
NH
H2N
O
H2N
O
CH3
4
3
Figure 1. Chemical structures of existing 5-HT3 receptor antagonists: (1)
ondansetron, (2) azasetron, (3) zacopride, (4) pancopride.

R. Mahesh et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6773–6776
6775
Table 1
Physical constants of quinoxalin-2-carboxamides
Compound
R
% Yielda
Mp in °C
Molecular formulab
log Pc
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
5
4o
4p
C6H5–
4-Me–C6H4–
4-MeO–C6H4–
C6H5–CH2–
C6H5–NH–
66.0
50.0
52.0
63.0
75.0
60.0
64.0
52.0
59.0
56.0
69.0
80.0
69.0
58.0
70.0
63.0
54.0
170–171
178–180
176–178
140–142
145–147
164–166
166–168
238–240
151–153
240–241
183–185
214–216
44–47
C15H11N3O
C16H13N3O
C16H13N3O2
C16H13N3O
C15H12N4O
C17H13N3O2
C15H10ClN3O
C15H10N4O3
C16H12ClN3O
2.43
2.92
2.31
2.50
1.95
1.75
2.99
2.40
3.48
3.63
3.24
3.24
1.59
2.01
1.32
1.90
2.32
3-Ac–C6H4–
3-Cl–C6H4–
4-NO2–C6H4–
3-Cl-2-CH3–C6H3–
Benzothiazol-2-yl–
4-Benzamido-phenyl–
2-Benzamido-phenyl–
CH3CH2CH2–
CH3CH2CH2CH2–
Pyrrolidine
C
C
C
16H10N4OS
22H16N4O2
22H16N4O2
C12H13N3O
C13H15N3O
45–50
96–98
68–70
98–100
C
C
C
13H13N3O
14H15N3O
15H17N3O
Cyclopentyl–
Cyclohexyl–
a
b
c
Yields are calculated after recrystallization with ethanol/diethyl ether.
Elemental (C, H, and N) analysis indicated that the calculated and observed values were within the acceptable limits ( 0.4%).
log P values were calculated using ChemBioDraw Ultra 11 (Cambridge Software).
Table 2
Pharmacological data of quinoxalin-2-carboxamides
Compound
Antagonism to
Duration of immobility in seconds (FST)b
Dose, mg/kg (ip)
Locomotor scoresb (10 min)
Dose, mg/kg (ip)
2-Me-5-HT (pA2)a
1.0
0.5
2.0
1.0
0.5
2.0
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
5
4o
6.8
5.2
5.0
5.7
5.8
6.1
5.8
5.0
7.6
4.5
4.9
4.0
6.7
7.3
6.4
6.5
6.0
6.9
—
141.00 06.20
105.00 04.90*
143.50 06.70
133.00 08.00
95.40 03.60*
132.40 04.90
151.20 07.30
106.32 04.80*
95.42 03.90*
115.10 06.40
125.00 07.60
121.00 04.00
92.33 03.70*
97.50 06.60*
139.00 06.90
94.25 06.40*
92.85 04.60*
100.40 10.0*
—
—
379.10 19.00
390.00 12.30
339.00 19.00
374.50 19.50
398.23 16.23
342.00 22.2
374.50 14.60
401.32 13.20
379.00 12.23
392.00 11.00
367.66 16.00
400.00 12.00
389.00 20.12
389.12 16.60
394.22 24.00
379.00 16.12
395.23 12.30
388.12 10.30
—
—
140.00 14.80
—
97.23 09.70*
383.63 17.85
—
—
387.00 19.70
—
—
397.23 17.00
387.93 19.45
—
—
—
387.45 18.89
381.00 11.83
—
390.00 12.30
388.58 14.70
368.00 12.00
380.26 21.66
392.63 16.23
—
—
384.00 19.55
—
—
408.15 18.50
383.33 16.32
—
—
—
385.63 12.70
379.39 18.25
—
382.00 13.69
396.00 24.32
400.00 22.00
—
—
—
126.00 07.20*
121.00 05.03*
—
—
—
—
142.00 10.40
120.00 05.19*
—
—
—
108.00 07.30*
147.00 10.00
—
—
—
148.00 03.05
121.00 12.10*
—
125.00 03.05*
103.00 20.30*
—
125.00 13.20*
119.00 10.50*
130.20 18.20*
171.00 06.60
120.00 06.05*
99.00 03.60*
95.10 06.50*
4p
Ondansetron
Control
Data were analyzed by graph pad prism (3) software through one-way ANOVA followed by post hoc Dunnett’s test.
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.
b
*
p <0.05 compared with vehicle-treated group (control).
possess antagonism lesser than that of acetyl group compound. On
the other hand, incorporation of both electron-withdrawing (chlo-
rine) and -releasing (methyl) groups on the benzene ring resulted
in the highly lipophilic and most potent compound 4i,26 pA2 7.6.
With these results it was interpreted that the role of aromatic
group in 5-HT3 receptor antagonists may be due to hydrophobic
interaction and not due to charge transfer complex with serotonin
Based on these results it was decided to couple the less bulky
hydrophobic amine with quinoxalin-2-carboxylic acid, by replac-
ing aniline with aliphatic amine, n-propylamine to serve the role
of benzene (aromatic group) in 5-HT3 receptor antagonists (qui-
noxalin-2-carboxamides). The obtained new chemical entity 4m
retained its antagonism and the pA2 value 6.7 was almost equal
to that of compound 4a, but lesser than that of the standard 5-
HT3 receptor antagonist. Higher homologation of aliphatic amine,
that is, propylamine into butylamine, furnished another potent
carboxamide 4n,27 whose pA2 value 7.3 was greater than that of
the standard drug. Ring-chain transformation of butylamine into
pyrrolidine afforded the carboxamide, 5, which retained antago-
nism; similar effects were obtained with amines such as cyclopen-
tylamine and cyclohexylamine, whose pA2 values were 6.5, 6.4 and
6.0, respectively. These results suggested that the role of aromatic
group in 5-HT3 receptor antagonists for the interaction with 5-HT3
receptor may be due to hydrophobic interaction. Since, the replace-
type
3 receptor, because compounds with electron-releasing
groups and compounds with electron-withdrawing groups failed
to show increased antagonism as compared to compound with
no substituent on the benzene ring. With this hypothesis, we cou-
pled the highly lipophilic bulky aromatic amines such as 2-amino-
benzothiazole, N-benzoyl-p-phenylenediamine and N-benzoyl-o-
phenylenediamine with quinoxalin-2-carboxylic acid, and the
formed carboxamides drastically lost their potency and their pA2
values were 4.5, 4.9 and 4.0, respectively. This may be due to steric
interaction imparted by the bulky group present in the amine.

6776
R. Mahesh et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6773–6776
ment of aromatic amine with aliphatic amines maintained the po-
tency of 5-HT3 receptor antagonists. However, to get the conclusive
results quinoxaline ring should be replaced with non-aromatic
group, which will be the futuristic extension of the work.
Acknowledgments
We thank the University Grants Commission (UGC), India, Birla
Institute of Technology & Science (BITS), Pilani, India, and SAIF,
Panjab University, Chandigarh, India, for providing the financial
support, laboratory and analytical facilities, respectively.
Regardless of their potency of 5-HT3 receptor antagonism, all
the synthesized molecules were subjected for their anti-depressant
potentials using forced swim test mice model.12,28 Test compounds
were administered through intra-peritoneal route of a dose of
1 mg/kg body weight. This preliminary study showed compounds
4m, 4p, 4o, 4e, 4i and 4n significantly reduced the duration of
immobility as compared to the vehicle-treated (control) group, fol-
lowed by compounds 4b and 4h. The compounds 4m, 4p, 4o, 4e, 4i
and 4n are more potent than the standard 5-HT3 receptor antago-
nist, ondansetron. The drug-induced psychomotor stimulation may
increase or decrease the swimming behavior in mice FST. To find
out this effect, all the screened molecules were tested for sponta-
neous locomotor activity using actophotometer.12 Interestingly,
none of the test compound influenced the locomotion of mice as
observed in spontaneous locomotor activity (Table 2).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.08.128.
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20. Mahesh, R.; Perumal, R. V.; Pandi, P. V. Biol. Pharm. Bull. 2004, 2, 1403.
21. Venkatesha Perumal, R.; Mahesh, R. Bioorg. Med. Chem. Lett. 2006, 16, 2769.
22. Harms, E. Org. Process Res. Dev. 2004, 8, 666.
23. Mac Kay, D. J. Pharm. Pharmacol. 1978, 30, 312.
24. Paton, W. D. M.; Zar, A. M. J. Physiol. 1968, 194, 13.
25. Compound 4a: Yield: 66%; mp: 170–171 °C; IR (KBr, m
max, cmÀ1): 3340 (sharp
N–H str.), 3105, 3060 (aromatic C–H str.), 1670 (C@O str.) 1590, 1480 (C@C,
C@N ring str.), 1560 (N–H bend), 1080 (C–N str.); 1H NMR (CDCl3) d 9.85 (s, 1H,
NH), 9.78 (s, 1H, quinoxaline), 8.23 (m, 2H, quinoxaline), 7.93 (m, 4H, 2H
quinoxaline, 2H benzene), 7.45 (m, 2H, benzene), 7.22 (m, 1H, benzene); Mass
spectra (ESI) of the compound exhibited the molecular ion peak at m/z 250
(M+1)+.
26. Compound 4i: Yield: 59%; mp: 151–153 °C; IR (KBr, m
max, cmÀ1): 3350 (sharp
N–H str.) 3150, 3050, (aromatic C–H str.), 1680 (C@O str.) 1600, 1460 (C@C,
C@N ring str.), 1540 (N–H bend) 1460, (CH3 bend); 1H NMR (CDCl3) d 9.94 (s,
1H, NH), 9.76 (s, 1H, quinoxaline), 8.24 (m, 3H, 2H, quinoxaline, 1H, benzene),
7.94 (m, 2H, quinoxaline), 7.26 (m, 2H, benzene), 2.51 (s, 3H, methyl). Mass
spectra (ESI) of the compound exhibited the molecular ion peak at m/z 320
(M+Na)+.
27. Compound 4n: Yield: 58%; mp: 45–50 °C; IR (KBr, m
max, cmÀ1): 3285 (sharp N–
H str.), 3080, 3060 (aromatic C–H str.), 2980, 2953 (aliphatic C–H str.), 1645
(C@O str.) 1590, 1490 (C@C, C@N ring str.), 1560 (N–H bend); 1H NMR (CDCl3)
d
9.68 (s, 1H, quinoxaline), 8.19 (dd, 1H, quinoxaline), 8.12 (dd, 1H,
quinoxaline), 8.02 (s, 1H, NH) 7.88 (m, 2H, quinoxaline), 3.59 (q, 2H,
NHCH2CH2CH2CH3), 1.73 (quin, 2H, NHCH2CH2CH2CH3), 1.52 (sex,
NHCH2CH2CH2CH3) 1.01 (t, 3H, NHCH2CH2CH2CH3); Mass spectra (ESI) of the
compound exhibited the molecular ion peak at m/z 230 (M+1)+.
28. Porsolt, R. D.; Bertin, A.; Jalfre, M. Arch. Int. Pharmacodyn. Ther. 1977, 229, 327.